Novel dry powder inhalation system for transpulmonary administration

ABSTRACT

The present invention provides a novel dry powder inhalation system suitable for transpulmonary administration. The dry powder inhalation system of the present invention characterized by using a combination of: (1) a vessel housing a freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form, and has: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) a property of becoming fine particles having a mean particle diameter (mass median aerodynamic diameter) of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec; and (2) a device comprising a member capable of applying said air impact to the freeze-dried composition in said vessel, and a member for discharging the powder-form freeze-dried composition that has been made into fine particles.

TECHNICAL FIELD

The present invention relates to a novel dry powder inhalation systemsuitable for transpulmonary administration. More specifically, thepresent invention relates to a dry powder inhalation system fortranspulmonary administration according to which a freeze-driedcomposition provided housed in a vessel can be prepared into a formsuitable for transpulmonary administration by being made into fineparticles at the time of use, and administered by inhalation as is.

Furthermore, the present invention encompasses the following inventionsrelated to the dry powder inhalation system for transpulmonaryadministration. Specific examples of these inventions include afreeze-dried composition which can be made into fine particle powdersuitable for transpulmonary administration (dry powdered preparation fortranspulmonary administration) at the time of use, a method forproducing the dry powdered preparation for transpulmonaryadministration, a method for transpulmonary administration by inhalationusing the freeze-dried composition and use of a freeze-dried compositionfor preparing a dry powdered preparation for transpulmonaryadministration at the time of use.

Hereinafter, in this specification, the term “fine particles” includessubstances having a fine structure regardless of a form such as a powder(particle powder) form, a needle-like form, a plate-like form and afibrous form.

BACKGROUND ART

In general, with regard to transpulmonary administration, it is knownthat the active ingredient contained in a medicine can be delivered intothe lungs efficiently by making the mean particle diameter of the activeingredient be 10 microns or less, preferably 5 microns or less. Thecurrent situation with conventional inhalations for transpulmonaryadministration is thus that, to make the medicine have a particlediameter suitable for transpulmonary administration in advance, fineparticles are prepared by a spray drying method, a jet milling method orthe like, and possibly further processing is carried out, and then thefine particles are provided filled into a dry powder inhaler.

Specifically, previously employed preparations include three types ofdry powder inhalation, namely (1) a preparation comprising a powder-formcomposition comprising only medicinal fine particles filled into asuitable vessel, (2) a preparation comprising a powder-form compositionin which medicinal fine particles have been granulated gently to form arelatively large particle diameter filled into a suitable vessel, and(3) a preparation comprising a powder-form composition comprising mixedparticles in which medicinal fine particles and vehicle particles(lactose etc.) having a particle diameter larger than the medicinal fineparticles are mixed together uniformly filled into a suitable vessel(refer to, for example, Japanese Unexamined Patent Publication No.1999-171760). Moreover, it is disclosed that if these powderedinhalations are administered into the respiratory tract, then thebehavior shown is that with (1) the medicinal fine particles in thecomposition reach the lower respiratory tract, for example the tracheaand the bronchi, and are deposited here, with (2) the granulatedmedicine separates into fine particles in flight in the respiratorytract, and the medicinal fine particles produced reach the lowerrespiratory tract, for example the trachea and the bronchi, and aredeposited here, and with (3) the vehicle is deposited in the oralcavity, on the pharynx or on the larynx, and the medicinal fineparticles only reach the lower respiratory tract, for example thetrachea and the bronchi, and are deposited here.

In this way, with a conventional powdered inhalation for transpulmonaryadministration, the ingredient to be inhaled is made into desirable fineparticles in advance, and then these fine particles, or else these fineparticles further processed by some methods, are filled into a drypowder inhaler, and transpulmonary administration is carried out usingthis.

To make a low-molecular-weight drug into fine particles, a spray dryingmethod (for example, disclosed in Japanese Unexamined Patent PublicationNo. 1999-171760), a jet milling method (for example, disclosed inJapanese Unexamined Patent Publication No. 2001-151673) or the like isusually used. The jet milling method comprises applying an air impacthaving an air flow rate of at least 1000 L/min and an air speed not lessthan the sonic speed to a low-molecular-weight drug to make the druginto fine particles. No method is known which makes the drug into fineparticles by a low air impact.

For a high-molecular-weight drug such as a peptide or protein, on theother hand, for example a method in which a spray solution of amedicinal stock liquid containing additives is subjected to spraydrying, thus making the stock liquid into fine particles having a meanparticle diameter of 5 microns or less in one step, and then these fineparticles are filled into a dry powder inhaler (spray drying method: WO95/31479), and a method in which a peptide or protein is freeze-driedalong with additives, and then the freeze-dried composition is made intofine particles by jet milling or the like, and these fine particles arefilled into a dry powder inhaler (freeze drying-jet milling method: WO91/16038) are known.

However, conventional powdered inhalations for transpulmonaryadministration prepared by the above-mentioned spray drying method orfreeze drying-jet milling method are not necessarily ideal preparationsfor high-molecular-weight drugs such as peptides and proteins inparticular. For example, as shown by the disclosure in WO 95/31479 thatabout 25% deactivation of interferon occurs during the spray dryingprocess, it is anticipated that if the spray drying method is used, thenproteins and the like will be deactivated in the manufacturing processand the activity of the drug will thus decrease. No method is knownwhich makes a high-molecular-weight drug into fine particles by a lowair impact, the same as a low-molecular-weight drug.

Moreover, with both the spray drying method and the freeze drying-jetmilling method, an operation is required in which the fine powderprepared is collected from the spray drying apparatus or jet millingapparatus and is subdivided and filled into vessels. It is thusinevitable that, accompanying this operation, problems will arise suchas the yield of the preparation decreasing due to collection or fillingloss and the cost rising correspondingly, and the preparation beingcontaminated with impurities. Moreover, in general it is difficult tosubdivide and fill the powder in small amounts with good accuracy. Ifthe spray drying method or the freeze drying-jet milling method, forwhich such subdividing and filling of small amounts in powder form isessential, is used, then it is thus necessary to establish a method offilling with small amounts and good accurancy of powder. In actual fact,details of a system, apparatus and method for filing with a fine powderare disclosed in U.S. Pat. No. 5,826,633.

DISCLOSURE OF THE PRESENT INVENTION

It is an object of the present invention to solve the various problemsof the above-mentioned conventional powdered inhalations fortranspulmonary administration. Specifically, it is an object of thepresent invention to provide a novel preparation system andadministration system that enables a freeze-dried composition that hasbeen housed in vessels to be made into fine particles down to a particlediameter suitable for transpulmonary administration in the vessel, andthen be used for transpulmonary administration by inhalation as is.

The present inventors carried out assiduous studies to attain the aboveobject, and as a result discovered that if a pharmacologically activesubstance as active ingredients is filled as a liquid into vessels andthen freeze-dried, then the non-powder-form freeze-dried compositionthus prepared can unexpectedly be made into fine particles by arelatively low air impact while still housed in the vessel. Based onthis knowledge, the present inventors carried out further studies, andas a result discovered that by using a freeze-dried composition, whichhas been housed in a non-powder form in a vessel, combined with a devicecomprising member for introducing air at a prescribed speed and flowrate into the vessel so as to be capable of applying a prescribed airimpact to the composition, and member for discharging from the vesselthe powdered composition that has been made into fine particles, thenthe freeze-dried preparation can be prepared into a fine particle powderform suitable for transpulmonary administration easily by a user at thetime of use (specifically, at the time of inhalation), and thus,transpulmonary administration can be carried out by administering thefine particle powder as is by inhalation. Moreover, the presentinventors discovered that a composition liquid containingpharmacologically active substances to be filled as a liquid intovessels can be prepared as a freeze-dried composition capable of beingmade into fine particles suitable for transpulmonary administrationthrough a predetermined air impact, and further discovered that this isnot limited to the case where the ingredients in particular to be thepharmacologically active substance as an active ingredient are clearlydissolved or mixed in a solvent, and moreover, the ingredients may benot dissolved or only partially dissolved (which state is called as “thenon-dissolved form”) in the solvent.

It was verified that, according to this transpulmonary administrationsystem, all of the previously mentioned problems of conventionalpowdered inhalations for transpulmonary administration can be solved.

That is, the above-mentioned transpulmonary administration system of thepresent invention can be used for transpulmonary administration withoutthe problem of contamination, since it is not necessary to subdivide andfill the powder form freeze-dried composition which was made into fineparticles in another device, into vessels.

Moreover, according to the above-mentioned administration system, activeingredients such as proteins or peptides are not exposed to hightemperature in the manufacturing process as is the case with the spraydrying method and the like, and hence there is no problem of thepharmacological activity dropping due to exposure to high temperature.This member that the administration system of the present invention isan extremely useful system in particular with pharmacologically activesubstances such as peptides and proteins that are expensive drugs, sincethe manufacturing cost can be reduced. More specifically, theadministration system of the present invention is economically useful.Moreover, according to the dry powder inhalation system of the presentinvention, an extremely high fine particle fraction (the amount of thedrug reaching the lungs: fine particle fraction, respirable fraction) isobtained, and hence the drug can be delivered into the lungsefficiently.

The dry powder inhalation system of the present invention ischaracterized by using a freeze-dried composition in a non-powdercake-like form prepared by subjecting active ingredients-containingcomposition liquid in the non-dissolved form to freeze-dry as apreparation for transpulmonary administration. The dry powder inhalationsystem of the present invention in which the freeze-dried composition ina cake-like form thus prepared is applied to a dry powder inhaler iscapable of achieving a significantly higher fine particle fractioncompared to the case where a preparation made into fine particle powderhaving a size suitable for transpulmonary administration using a methodemployed for powder inhalants heretofore known, such as a jet millingmethod or a spray drying method, is applied to a dry powder inhaler ofthe present invention. For such reasons, the dry powder inhalationsystem of the present invention can be ranked as a high-performancetranspulmonary administration system.

The present invention was developed based on this knowledge, andincludes the following items.

Item 1. A freeze-dried composition for transpulmonary administrationprepared by freeze-drying a composition liquid containing ingredients ina non-dissolved form which has the following properties (i) to (iii):

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) becoming fine particles having a mean particle diameter (massmedian aerodynamic diameter) of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate of at least 17 ml/sec.

Item 2. The freeze-dried composition according to Item 1, wherein ahigh-molecular-weight drug is contained as an active ingredient.

Item 3. A method of manufacturing a dry powdered preparation fortranspulmonary administration, comprising:

introducing air into a vessel to apply to a freeze-dried composition anair impact having an air speed of at least 1 m/sec and an air flow rateof at least 17 ml/sec using a device capable of applying said air impactto the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles havinga mean particle diameter (mass median aerodynamic diameter) of 10microns or less or a fine particle fraction of 10% or more;

the freeze-dried composition prepared by freeze-drying a compositionliquid containing ingredients in a non-dissolved form and having thefollowing properties:

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) becoming fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof the air impact.

Item 4. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to Item 3, wherein thefreeze-dried composition contains a high-molecular-weight drug as anactive ingredient.

Item 5. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to Item 3 comprising pulverizinga freeze-dried composition into fine particles using a dry powderinhaler described under item (A) or (B) as a device:

(A) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding member for feedingair into the air jet flow path of said needle part, and an inhalationport that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding member, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path, or

(B) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

Item 6. A dry powder inhalation system for transpulmonaryadministration, using a combination of:

(1) a vessel housing a freeze-dried composition prepared byfreeze-drying a composition liquid containing ingredients in anon-dissolved form, and has:

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) a property of becoming fine particles having a mean particlediameter (mass median aerodynamic diameter) of 10 microns or less or afine particle fraction of 10% or more upon receiving an air impacthaving an air speed of at least 1 m/sec and an air flow rate of at least17 ml/sec; and

(2) a device comprising a member capable of applying said air impact tothe freeze-dried composition in said vessel, and a member fordischarging the powder-form freeze-dried composition that has been madeinto fine particles.

Item 7. The dry powder inhalation system for transpulmonaryadministration according to Item 6, wherein the vessel and the deviceare used in combination at the time of inhalation.

Item 8. The dry powder inhalation system for transpulmonaryadministration according to Item 6, wherein the freeze-dried compositioncontains a high-molecular-weight drug as an active ingredient.

Item 9. The dry powder inhalation system for transpulmonaryadministration according to Item 6, wherein the device is:

A) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding member for feedingair into the air jet flow path of said needle part, and an inhalationport that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding member, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path, or

B) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

Item 10. A transpulmonary administration method comprising:

making a freeze-dried composition into fine particles having a meanparticle diameter of 10 microns or less or a fine particle fraction of10% or more by applying an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec to the freeze-driedcomposition at the time of use, and

administering the resulting fine particle powder to a user byinhalation;

the freeze-dried composition being prepared by freeze-drying acomposition liquid containing ingredients in a non-dissolved form andhaving the following properties:

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) becoming fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof the air impact.

Item 11. The transpulmonary administration method according to Item 10,wherein the freeze-dried composition is housed in a vessel, and the fineparticle powder are prepared using a device comprising a member capableof applying the air impact to the freeze-dried composition in the vesseland a member for discharging the resulting fine particle powder-formfreeze-dried composition out of the vessel.

Item 12. The transpulmonary administration method according to Item 10,wherein the freeze-dried composition contains a high-molecular-weightdrug as an active ingredient.

Item 13. The transpulmonary administration method according to Item 11,using a dry powder inhaler described under item (A) or (B) as thedevice:

(A) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding member for feedingair into the air jet flow path of said needle part, and an inhalationport that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding member, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path, or

(B) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

Item 14. Use of a freeze-dried composition for transpulmonaryadministration by inhalation,

the freeze-dried composition prepared by freeze-drying a compositionliquid containing ingredients in a non-dissolved form and having thefollowing properties:

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) becoming fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec, and being used by forming into fineparticles having said mean particle diameter or said fine particlefraction.

Item 15. The use of a freeze-dried composition for transpulmonaryadministration according to Item 14, wherein the freeze-driedcomposition is housed in a vessel, and the fine particles are preparedusing a device comprising a member capable of applying the air impact tothe freeze-dried composition in the vessel and a member for dischargingthe resulting fine particle powder-form freeze-dried composition out ofthe vessel.

Item 16. The use of a freeze-dried composition for transpulmonaryadministration according to Item 14, wherein the freeze-driedcomposition contains a high-molecular-weight drug as an activeingredient.

Item 17. Use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration by inhalation,the freeze-dried composition having the following properties:

(i) being prepared by freeze drying a composition liquid containingingredients in the non-dissolved form,

(ii) a non-powder cake-like form,

(iii) a disintegration index of 0.05 or more, and

(iv) becoming fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec,

and being used by forming into fine particles having said mean particlediameter or said fine particle fraction at the time of use.

Item 18. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration by inhalationaccording to Item 17, wherein the freeze-dried composition contains ahigh-molecular-weight drug as an active ingredient.

Item 19. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to Item17, wherein the freeze-dried composition is housed in a vessel, and thefine particles are prepared by using a device comprising a member forapplying a prescribed air impact to the freeze-dried composition housedin the vessel and a member for discharging the resulting fine particlepowder form freeze-dried composition out of the vessel.

Item 20. Use of a composition liquid containing ingredients in thenon-dissolved form for manufacture of a freeze-dried composition havingthe following properties, which is used for manufacture of dry powderedpreparation for transpulmonary administration:

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) becoming fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec, and being used by forming into fineparticles having said mean particle diameter or said fine particlefraction at the time of use.

Item 21. The use of a composition liquid containing ingredients in thenon-dissolved form according to Item 20, wherein the freeze-driedcomposition contains a high-molecular-weight drug as an activeingredient

Item 22. The use of a composition liquid containing ingredients in thenon-dissolved form according to Item 20, wherein the freeze-driedcomposition is housed in a vessel, and the fine particles are preparedby using a device comprising a member for applying a prescribed airimpact to the freeze-dried composition housed in the vessel and a memberfor discharging the resulting fine particle powder form freeze-driedcomposition out of the vessel.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross section showing a dry powder inhaler (jet type 1) ofthe present invention disclosed as Embodiment 1. Note that, in thedrawing, the arrows indicate the flow of external air (likewise in FIGS.2 and 3 below).

Moreover, the meanings of the various reference numerals are as follows:1. vessel, 1 a. stopper, 2. freeze-dried composition, 3. air jet flowpath, 4. discharge flow path, 5. needle part, 6. inhalation port, 7. airintake member, 8. tubular safety cover, 9. air pressure-feeding member,10. bellows body, 11. intake valve, 12. intake port, 13. dischargevalve, 14. discharge port, 15. connecting port (likewise in FIGS. 2 to11 below).

FIG. 2 is a cross section showing a dry powder inhaler (self-inhalingtype 1) of the present invention disclosed as Embodiment 2. Moreover,the meanings of the various reference numerals are as follows: 16.suction flow path, 17. air introduction flow path, 18. inhalation port,19. air intake member (likewise in FIG. 3 below).

FIG. 3 is a cross section showing a dry powder inhaler (self-inhalingtype 2) of the present invention disclosed as Embodiment 3.

FIG. 4 is a perspective view showing a dry powder inhaler (self-inhalingtype 3) of the present invention disclosed as Embodiment 4. Moreover,the meanings of the reference numerals areas follows: 21. housing, 22.holder part, 27. lid, 28. window, 32. mouthpiece, 32 a. mouthpiece cap,39. connector (likewise in FIGS. 5 to 13 below).

FIG. 5 is a cross section of the above-mentioned dry powder inhaler(self-inhaling type 3). Moreover, the meanings of the reference numeralsare as follows: 20. housing chamber, 21A. hinge, 23. guide part, 24.holder operating part, 26. housing main body, 29. introduction port, 30.check valve, 31. suction port, 33. partition part, 35. remover, 36.lever, 37. mechanism part, 39. connector, 40. hinge, 41. hinge (likewisein FIGS. 6 to 13 below).

FIG. 6(a) is across section of part of the above-mentioned dry powderinhaler (self-inhaling type 3). FIG. 6 (b) is a side view of the needlepart of this dry powder inhaler. Moreover, the meanings of the referencenumerals are as follows: 16 a. tip opening of suction flow path 16, 17a. tip opening of air introduction flow path 17, 34. peripheral wallpart, 42. second introduction path, 42 a. introduction groove inpartition part 33, 42 b. introduction groove in peripheral wall part 34,43. gap, 44. one end of second introduction path 42, 45. other end ofsecond introduction path 42, 46. vent hole, 47. wall (likewise in FIGS.7 to 13 below).

FIGS. 7 to 10 are sectional view for explaining the operation of theabove-mentioned dry powder inhaler (self-inhaling type 3). Referencenumeral 25 indicates a removal/insertion port.

FIG. 11 is a perspective view of a dry powder inhaler (self-inhalingtype 4), which is another embodiment of the present invention. Referencenumeral 48 indicates an operator.

FIG. 12 is a perspective view of a dry powder inhaler (self-inhalingtype 5) of another embodiment of the present invention. Referencenumeral 49 indicates an operator.

FIG. 13 is a perspective view of a dry powder inhaler (self-inhalingtype 5) of another embodiment of the present invention. Referencenumeral 49 indicates an operator.

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Freeze-Dried Composition

The freeze-dried composition of the present invention is a compositionthat is prepared in a non-powder dry form by filling composition liquidcontaining ingredients in the non-dissolved form into a vessel and thenfreeze-drying the same as is. The freeze-dried composition is preparedby freeze-drying composition liquid in the non-dissolved form containingpreferably a single or a plurality of effective doses of activeingredients, and in particular, preferably a single dose of effectivedose of active ingredients.

The freeze-dried composition of the present invention is prepared byselecting a composition (types and amounts of active ingredient andcarrier used together with the active ingredient) of the compositionliquid such that the disintegration index of the freeze-driedcomposition prepared is 0.05 or more, and thus the freeze-driedcomposition can be made into fine particles down to a particle diametersuitable for transpulmonary administration in an instant by receiving animpact of external air (air impact, jet pressure) introduced into(flowing into) the vessel.

Note that the disintegration index in the present invention is a valuecharacteristic of the freeze-dried composition that can be obtained bymeasuring following the undermentioned method.

<Disintegration Index>

0.2 to 0.5 ml of a mixture containing target components that willconstitute the freeze-dried composition is filled into a vessel having atrunk diameter of 18 mm or 23 mm, and freeze-drying is carried out.Next, 11.0 ml of n-hexane is instilled gently down the wall of thevessel onto the non-powder-form freeze-dried composition obtained.Agitation is carried out for about 10 seconds at 3000 rpm, and then themixture is put into a UV cell of optical path length 1 mm and opticalpath width 10 mm, and the turbidity is measured immediately at ameasurement wavelength of 500 nm using a spectrophotometer. Theturbidity obtained is divided by the total amount (weight) of thecomponents constituting the freeze-dried composition, and the valueobtained is defined as the disintegration index.

Here, an example of the lower limit of the disintegration index of thefreeze-dried composition of the present invention can be given as theabove-mentioned 0.05, preferably 0.08, more preferably 0.09, yet morepreferably 0.1, still more preferably 0.11, still further preferably0.12, and in particular 0.13 is preferable.

Moreover, there is no particular limitation on the upper limit of thedisintegration index of the freeze-dried composition of the presentinvention, but an example can be given as 1.5, preferably 1, morepreferably 0.9, yet more preferably 0.8, and still more preferably 0.7.In particular, 0.6 is preferable, and 0.5 is more preferable. Thefreeze-dried composition of the present invention preferably has adisintegration index in a range constituted from a lower limit and anupper limit selected as appropriate from the above, with the provisothat the disintegration index is at least 0.05. Specific examples of therange of the disintegration index are 0.05 to 1.5, 0.08 to 1.5, 0.09 to1.0, 0.1 to 0.9, 0.10 to 0.8, 0.1 to 0.7, 0.1 to 0.6 and 0.1 to 0.5.

Moreover, it is preferable to prepare the freeze-dried composition ofthe present invention in a non-powder cake-like form by freeze-drying.In the present invention, ‘non-powder-form freeze-dried composition’member a dry solid obtained by freeze-drying a composition liquidcontaining active ingredients, and is generally called a ‘freeze-driedcake’. However, even if cracks appear in the cake, the cake breaks intoa plurality of large lumps, or part of the cake breaks into a powderduring the freeze-drying process or during subsequent handling, thiscake is still included as a non-powder-form freeze-dried compositionthat is the subject of the present invention, more specifically, as afreeze-dried composition having a non-powder cake like form, providedthe effects of the present invention are not impaired.

As described above, the freeze-dried composition of the presentinvention is prepared by freeze-drying a composition liquid containingingredients in the non-dissolved form and has a disintegration index of0.05 or more and a non-powder cake-like form and becomes fine particleshaving a mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate of at least 17 ml/sec, onthe basis of properties peculiar to the freeze-dried compositionrepresented by the disintegration index.

A preferable freeze-dried composition is such that, upon receiving theabove air impact, the mean particle diameter becomes 10 microns or lessand preferably 5 microns or less or a fine particle fraction of 10% ormore, preferably 20% or more, more preferably 25% or more, still morepreferably 30% or more, and especially more preferably 35% or more.

As described above, the air impact applied to a freeze-dried compositionis not limited, as long as it is generated by air having an air speed ofat least 1 m/sec and an air flow rate of at least 17 ml/sec. Specificexamples of an air impact include an impact generated by an air having aspeed of 1 m/sec or more, preferably 2 m/sec or more, more preferably 5m/sec or more and a still more preferably 10 m/sec or more. Here, thereis no limitation on the upper limit of the air speed, but it isgenerally 300 m/sec, preferably 250 m/sec, more preferably 200 m/sec andyet more preferably 150 m/sec. The air speed is not limited as long asit is arbitrary selected from the range extending from a lower limit toan upper limit; however, the ranges of 1 to 300 m/sec, 1 to 250 m/sec, 2to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200 m/sec or 10 to150 m/sec can be given as examples.

Examples of the air impact include those generated by air having an airflow rate of generally 17 ml/sec or more, preferably 20 ml/sec or moreand more preferably 25 ml/sec or more. There is no limitation on theupper limit of the air flow rate; however, the air flow rate isgenerally 900 L/min, preferably 15 L/sec, more preferably 5 L/sec andyet more preferably 4 L/sec. Especially, 3 L/sec is very preferable.More specifically, the air flow rate is not limited as long as it isselected from the range extending from a lower limit to an upper limit;however, examples of such a range include 17 ml/sec to 15 L/sec, 20ml/sec to 10 L/sec, 20 ml/sec to 5 L/sec, 20 ml/sec to 4 L/sec, 20ml/sec to 3 L/sec and 25 ml/sec to 3 L/sec.

In principle, there is no particular limitation on the activeingredients used in the present invention, provided it is a substancehaving some pharmacological activities (pharmacologically activesubstance: hereinafter, simply referred to as a drug) that can be usedas ingredients for a powdered inhalation for transpulmonaryadministration; nevertheless, low-molecular-weight drugs andhigh-molecular-weight drugs can be given as specific examples. Suchhigh-molecular weight drugs include physiologically active substancessuch as proteins (including peptides or polypeptides), for example,enzymes, hormones, antibodies, etc., nucleic acids (including genes andcDNA), RNA, and the like.

Moreover, regarding the disease targeted by the drug, both whole bodytreatment and local treatment can be envisaged, depending on the case.

Examples of low-molecular-weight drugs include, for example,hydrocortisone, prednisolone, triamcinolone, dexamethasone,betamethasone, beclometasone, fluticasone, mometasone, budesonide,salbutamol, salmeterol, procaterol, buprenorphine hydrochloride,apomorphine, taxol, and antibiotics such as tobramycin.

Examples of high-molecular-weight drugs (physiologically activesubstances such as proteins and nucleic acids) include, for example,interferons (α, β, γ), interleukins (for example, interleukin-1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, etc.),anti-interleukin-1α antibody, interleukin-1 receptor, interleukinreceptor antagonist, interleukin-4 receptor, anti-interleukin-2antibody, anti-interleukin-6 receptor antibody, interleukin-4antagonist, interleukin-6 antagonist, anti-interleukin-8 antibody,chemokine receptor antagonist, anti-interleukin-7 receptor,anti-interleukin-7 antibody, anti-interleukin-5 antibody, interleukin-5receptor, anti-interleukin-9 antibody, interleukin-9 receptor,anti-interleukin-10 antibody, interleukin-10 receptor,anti-interleukin-14 antibody, interleukin-14 receptor,anti-interleukin-15 antibody, interleukin-15 receptor, interleukin-18receptor, anti-interleukin-18 antibody, erithropoietin (EPO),erithropoietin derivatives, granulocyte colony stimulating factor(G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF),macrophage colony stimulating factor (M-CSF), calcitonin, insulin,insulin derivatives (Lis Pro, NovoRapid, HOE901, NN-304, etc.),insulintropin, insulin-like growth factor, glucagon, somatostatin andanalogs thereof, vasopressin and analogs thereof, amylin, human growthhormone, luteinizing hormone releasing hormone, follicle stimulatinghormone, growth hormone releasing factor, parathyroid hormone,endothelial cell growth factor, platelet derived growth factor,keratinocyte growth factor, epidermal growth factor, fibroblast growthfactor, brain-derived neurotrophic factor, ciliary neurotrophic factor,tumor necrosis factor (TNF), TNF receptor, TNF inhibitor, transforminggrowth factor (TGF), hepatocyte growth factor (HGF), nerve growth factor(NGF), blood stem cell growth factor, platelet growth simulator,naturiuretic peptide, blood coagulation factor, blood hepatocyte growthfactor (S-CSF), FLT3 ligand, anti-platelet aggregation inhibitingmonoclonal antibody, tissue plasminogen activator and derivativesthereof, superoxide dismutase, antisense drugs, immunosuppression agents(for example, cyclosporin, tacrolimus hydrate, etc.), cancer repressorgene p53, cystic fibrosis transmembrane conductance regulator (CFTR)gene, RNA interferance (RNAi), Bridged Nucleic Acid (BNA), α-1antitrypsin, thrombopoietin (TPO), metastatin, deoxyribonuclease(Dnase), prolactin, oxytocin, thyrotopin releasinghormone (TRH),bactericidalpermeability increasing (BPI) protein, and vaccinepreparations, for example influenza vaccines, AIDS vaccines, rotavirusvaccines, malaria vaccines and tuberculosis vaccines such as Mtb72f.

One of these active ingredients can be used alone, or two or more can beused in combination. Note that the various peptides above encompassnatural polypeptides, gene recombinant polypeptides, chemicallysynthesized polypeptides and so on.

These active ingredients can be used in free form or in salt form,alternatively, they can be used in a form such that they are bound byvarious types of hosts. Such hosts are not particularly limited insofaras active ingredients (for example, high-molecular-weight drugs such asproteins and nucleic acids, etc., low-molecular weight drugs) can bebound by various forms of adhesion/presence (adsorption, absorption,clathration, ionic interactions, etc.). Specific examples of hostsinclude lipid-membrane structures, microcapsules, cyclodextrins,dendrimers, microsperes, nanocapsules, nanosperes, etc. Lipid-membranestructures include liposomes such as single membrane liposomes,multilayer lipospmes, etc.; emulsions such as the O/W-type or W/O/W-typeetc., spherical micelles, corded micelles, layer structural substance,etc.

In general, dendrimers are molecules with a three-dimensional form suchthat molecule chains regularly branch outwardly from a core regularlybased on a predetermined rule. Dendrimers generally have a sphericalstructure with voids for encapsulting drugs therein, and thus can serveas nanocapsules. The following methods are known for encapsulting drugsin dendrimers: (1) utilizing interactions between the dendrimer interiorand drugs (hydrophobic interactions, electrostatic interactions, etc.)or (2) forming a dense shell structure at the dendrimer surface tophysically entrap drugs (Kenji Kawano: Drug Delivery System, 17-6,462-470(2002)). SuperFect employed in Examples is composed of activateddendrimer molecules of a predetermined form (Tang. M. X, Redemann, C. T.and Szoka, Jr. F. C: In vitro gene delivery by degraded polyamidoaminedendrimers. Bioconjugate Chem. 7, 703(1996)). These molecules have astructure branching from the center, and have positively charged aminesat the branch terminals so as to interact with the (negatively charged)phosphoric acid groups of nucleic acids. SuperFect is endowed with theproperty of compacting DNA or RNA so that DNA or RNA can be readilyintroduced into cells.

Preferably, hosts include liposomes, dendrimers, retrovirus vectors,adenovirus vectors, adeno-associated virus vectors, lentivirus, herpessimplex virus vector, HVJ (Sendai Virus)-liposome (for example, HVJEnvelope VECTOR KIT), etc.

Hosts such as lipid-membrane structures or dendrimers, etc. have beenwidely used for introducing foreign genes into cells. Liposomes for genetransfer and dendrimers for gene transfer can also be used in thepresent invention in the same manner, and are available commercially.

Particle diameter (geometric mean particle diameter: Dynamic lightscattering or Laser diffraction/scattering) of the hosts is notparticularly limited insofar as it is 10 μm or less, and 5 μm or less ispreferred. In general, liposomes or emulsions, have for example, aparticle diameter (geometric mean particle diameter: Dynamic lightscattering or Laser diffraction/scattering) of 50 nm to a fewmicrometers, and spherical micelles have a particle diameter of 5 to 50nm.

For measuring the geometric mean particle diameter, in general, dynamiclight scattering is used for distribution of particles with the sizerange of several tens of nanometers and laser diffraction/scattering isused for ten or more microns. For distribution of particles with thesize in the range of hundreds of nanometers to several microns, eithermethod may be used.

The manner of binding active ingredients (for example, nucleic acidssuch as genes, etc.) into the hosts is not particularly limited. Forexample, when a lipid membrane structure is used, active ingredients areadhered to/present in the membrane, the membrane surface, the membraneinterior, the lipid layer inside or the lipid layer surface of themembrane structure.

Examples of methods for obtaining the bound forms include the method ofadding aqueous solvent to a dried mixture of the host such as a lipidmembrane structure, etc., and the active ingredients (genes, etc.), andthen emulsifying them with an emulsifier such as a homogenizer or thelike; the method of dissolving a host such as a membrane structure withan organic solvent, and evaporating the solvent to obtain a driedsubstance, and further adding aqueous solvent including genes to thedried substance obtained and emulsifying the mixture; the method ofadding aqueous solvent including active ingredients (genes, etc.) tohosts such as membrane structure substances dispersed in the aqueoussolvent; and a method for adding aqueous solvent including activeingredients (genes, etc.) to a dried substance obtained by dispersinghosts such as a membrane structural substance into aqueous solvent andthen drying them (Japanese Unexamined Published Patent No. 2001-02592).

The size (particle diameter) can be controlled by a method for carryingout extrusion (extrusion-filtration) under high pressure with a membranefilter having the uniform pore diameter, or by a method using anExtruder (Japanese Unexamined Patent Publication No. 1994-238142).

The freeze-dried composition of the present invention is prepared byfreeze-drying a composition liquid containing ingredients (including theabove-mentioned active ingredients) in then on-dissolved form. In thisspecification, ‘the non-dissolved form’ indicates a state whereingredients are neither clearly dissolved nor mixed in a solventconstituting a composition liquid. Such ‘non-dissolved form’ includes astate where solids in the solvent can be detected by various methods.More specifically, as an example, the case can be mentioned where solidshaving the geometric mean particle diameter (Dynamic light scattering orLaser diffraction/scattering) of 0.01 μm or more, preferably 0.05 μm ormore, more preferably 0.1 μm or more, still more preferably 0.2 μm ormore, still further preferably 0.5 μm or more can be detected. Accordingto the object of the present invention, the geometric mean particlediameter (Dynamic light scattering or Laser diffraction/scattering) ofthese solids are determined so that the upper limit thereof is 20 μm orless, preferably 15 μm or less, more preferably 10 μm or less. Morespecifically, the ‘non-dissolved form’ of the present invention includesa state where solids having the geometric mean particle diameter(Dynamic light scattering or Laser diffraction/scattering) having 0.01to 20 μm, 0.05 to 15 μm, 0.1 to 15 μm, 0.2 to 15 μm, 0.5 to 15 μm, 0.05to 10 μm, 0.1 to 10 μm, or 0.2 to 10 μm are present in the solvent andcan be detected by various methods. The ‘non-dissolved form’ includesthe following examples: a state where ingredients are not completelydissolved into the solvent, and are supersaturated; and a state whereingredients are not dissolved in the solvent, and more specifically,active ingredients which are not dissolved or are hard to dissolve intothe solvent are suspended or mudded in the solvent. The non-dissolvedform can be typically evaluated by measuring the turbidity of thesample, but can also be evaluated by methods for measuring the particlesize distribution of the non-dissolved substances in the solvent with anapparatus for particle size distribution measurement.

In the specification, ingredients in the non-dissolved form specifiesnot only the case where the active ingredients or the carrier, whichwill be described later, themselves are not dissolved in the solvent,but also the case where the active ingredients are dissolved in thesolvent and bound by a host such as the above-mentioned liposomes,microcapsules, cyclodextrins, dendrimers, etc., while the host such asliposome, etc., is not dissolved in the solvent. The type of ingredientsis not particularly limited insofar as the ingredients are in thedissolved-form, and may be active ingredients, hosts which are mixed inthe composition liquid with active ingredients or another ingredient(which will be described later).

The solvent constituting the composition liquid with the ingredients arenot particularly limited, and can include isotonic solutions such aswater, physical saline, etc., culture medium, buffer solutions, etc.Organic solvents may be contained in the solvent provided that the endproduct (freeze-dried composition for transpulmonary administration)adversely affects human body. Such organic solvents include methanol,ethanol, isopropanol, acetone, ethylene glycol, and the like.

The freeze-dried composition of the present invention may comprise theactive ingredient alone or the active ingredient and the host, as longas the end products satisfy the above-mentioned disintegration index, ora suitable carrier may be admixed. In the case of using a carrier inaddition to the active ingredient, there are no particular limitationson the type and amount of carrier used, so long as the finalfreeze-dried composition containing the carrier with active ingredientswhich is prepared by freeze-drying the composition liquid in thenon-dissolved form satisfies the following properties (i) to (iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec and the effects of the present invention(making into a fine particle) are attained. Those carriers commonly usedfor freeze-drying may be used arbitrarily and at desired amounts.

Specific examples of the carrier include hydrophobic amino acids such asvaline, leucine, isoleucine and phenylalanine, and salts and amidesthereof; hydrophilic amino acids such as glycine, proline, alanine,arginine and glutamic acid, and salts and amides thereof; derivatives ofamino acids; and dipeptides, tripeptides or the like having two or moreof the same one or different ones of the above-mentioned amino acids,and salts and amides thereof. One of these can be used alone, or two ormore can be used in combination. Here, examples of salts of the aminoacid or peptide include salts with an alkali metal such as sodium orpotassium or an alkaline earth metal such as calcium, and addition saltswith an inorganic acid such as phosphoric acid or hydrochloric acid oran organic acid such as sulfonic acid, while examples of amides includeL-leucine amide hydrochloride. Moreover, an amino acid other than anα-amino acid can be used in as a carrier. Examples of such an amino acidinclude β-alanine, γ-aminobutyric acid, homoserine and taurine.

Other examples of carriers include monosaccharides such as glucose;disaccharides such as saccharose, maltose, lactose and trehalose; sugaralcohols such as mannitol; oligosaccharides such as cyclodextrin;polysaccharides such as dextran 40 and pullulan; polyhydric alcoholssuch as polyethylene glycol; and fatty acid sodium salts such as sodiumcaprate. One of these carriers may be used alone, or two or more may beused in combination.

Of the above carriers, specific examples of carriers that are preferablefor delivering the active ingredient efficiently into the lungs includehydrophobic amino acids such as isoleucine, valine, leucine andphenylalanine, and salts and amides thereof; hydrophobic dipeptides suchas leucyl-valine, leucyl-phenylalanine and phenylalanyl-isoleucine; andhydrophobic tripeptides such as leucyl-leucyl-leucine andleucyl-leucyl-valine. Again, one of these may be used alone, or two ormore may be used in combination.

In the case of interferon γ, it is preferable to use basic amino acids,and salts and amides thereof, basic dipeptides and basic tripeptides incombination of hydrophobic amino acids, and salts and amides thereof,hydrophobic dipeptides, and hydrophobic tripeptides in view of makinginto fine particles and preparation stability. The basic amino acidsinclude arginine, lysine, histidine and salts thereof. The combinationof phenylalanine and arginine hydrochloride or the combination ofphenylalanine, leucine and arginine hydrochloride is preferable.

There are no particular limitations on the proportion of the activeingredient(s) (drug(s)) mixed into the freeze-dried composition;nevertheless, examples of the content are 20 mg or less, preferably 10mg or less, more preferably 5 mg or less, yet more preferably 2 mg orless, particularly preferably 1 mg or less.

Moreover, there are no particular limitations on the mixing proportionof the carrier(s), provided the final freeze-dried composition satisfiesthe above-mentioned properties (i) to (iii); nevertheless, as aguideline, per 100 wt % of the freeze-dried composition, the range isgenerally from 0.1 to less than 100 wt %, preferably from 1 to less than100 wt %, more preferably from 10 to less than 100 wt %, particularlypreferably from 20 to less than 100 wt %.

Note that, in addition to the above-mentioned components, thefreeze-dried composition that is the subject of the present inventionmay have mixed therein various additives, for example for stabilizingthe active ingredient(s) in solution before drying, for stabilizing theactive ingredient(s) after drying, or for preventing the activeingredient(s) from sticking to the vessel, provided that theabove-mentioned properties (i) to (iii) is satisfied and the effects ofthe present invention are not impaired. For example, the freeze-driedcomposition may contain human serum albumin, inorganic salts,surfactants, buffering agents and so on. A wide range of surfactants canbe used, regardless of whether they are anionic surfactants, cationicsurfactants or nonionic surfactants, provided that they are surfactantsthat are generally used in medicines. Preferable examples are nonionicsurfactants such as polyoxyethylene sorbitan fatty acid esters (forexample Tween type surfactants) and sorbitan trioleate.

The method of freeze-drying a composition liquid which contains suchactive ingredients and other ingredients is not particularly limited,and a freeze-drying method commonly used in preparing a usualfreeze-dried preparation (freeze-dried composition), such as aninjection which is dissolved at the time of usage can be employed. Thereis no limitation, and a quick freeze-drying method, if required, may becarried out by appropriately varying freeze-drying conditions.

The freeze-dried composition of the present invention can be pulverizedinto fine particles suitable for transpulmonary administration byapplying an air impact of a predetermined value. Thus, the freeze-driedcomposition of the present invention can be served as a so-calledpre-preparation for a powder preparation for transpulmonaryadministration, which is suitable for providing a powder preparation fortranspulmonary administration (a freeze-dried composition for providinga powder preparation for transpulmonary administration).

The freeze-dried composition for use in the present inventionencompasses the specific embodiments defined in the following items:

101. A freeze-dried composition for transpulmonary administration havingthe following properties (i) to (iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec.

102. The freeze-dried composition according to item 101, wherein thedisintegration index is 0.05 to 1.5.

103. The freeze-dried composition according to item 101, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receipt of an air impacthaving an air speed of at least 2 m/sec and an air flow rate of at least17 ml/sec.

104. The freeze-dried composition according to item 101, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receiving an air impacthaving an air speed in a range of 1 to 300 m/sec and an air flow rate ofat least 17 ml/sec.

105. The freeze-dried composition according to item 101, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receipt of an air impacthaving an air speed of at least 1 m/sec and an air flow rate of at least20 ml/sec.

106. The freeze-dried composition according to item 101, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receiving an air impacthaving an air speed of at least 1 m/sec and an air flow rate in a rangeof 17 ml/sec to 15 L/sec.

107. The freeze-dried composition according to item 101, becoming fineparticles having a mean particle diameter of 5 microns or less or a fineparticle fraction of 20% or more upon receiving an air impact.

108. The freeze-dried composition according to item 101, containing alow-molecular-weight drug as an active ingredient.

109. The freeze-dried composition according to item 101, containing ahigh-molecular-weight drug such as a protein, a peptide or the like asan active ingredient.

110. The freeze-dried composition according to item 109, containing anucleic acid as an active ingredient with held in a holder.

111. The freeze-dried composition according to item 108, containing alow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

112. The freeze-dried composition according to item 109, containing ahigh-molecular-weight drug such as a protein, a peptide or the like asthe active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

113. The freeze-dried composition according to item 111, containing alow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

114. The freeze-dried composition according to item 112, characterizedby containing a high-molecular-weight drug such as a protein, a peptideor the like as the active ingredient, and at least one selected from thegroup consisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

115. The freeze-dried composition according to item 101, being awater-soluble composition.

116. The freeze-dried composition according to item 101, containing asingle dose of an active ingredient.

117. The freeze-dried composition according to item 101, being afreeze-dried composition for transpulmonary administration prepared byfreeze-drying a composition liquid containing ingredients in thenon-dissolved form and has the following properties (i) to (iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.05 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed in a range of 1 to 300 m/secand an air flow rate in a range of 17 ml/sec to 15 L/sec.

118. The freeze-dried composition according to item 117, wherein the airspeed is 1 to 250 m/sec.

119. The freeze-dried composition according to item 117, wherein the airflow rate is 20 ml/sec to 10 L/sec.

(2) Method of Manufacturing a Dry Powdered Preparation

Moreover, the present invention relates to a method of manufacturing adry powdered preparation comprising fine particles with a particlediameter suitable for transpulmonary administration (dry powderedpreparation for transpulmonary administration) by inhalation, by makinga freeze-dried composition that has been housed in a non-powder form ina vessel into fine particles. The manufacturing method can beimplemented in the vessel housing the non-powder form freeze-driedcomposition by applying a predetermined air impact.

Specifically, the method of manufacturing the dry powder preparation ofthe present invention can be carried out by applying an air impacthaving an air speed of at least 1 m/sec and an air flow rate of at least17 ml/sec to the non-powder form freeze-dried composition of the presentinvention having a disintegration index of at lest 0.05 which isprepared by freeze-drying the composition liquid containing ingredientsin the non-dissolved form as described in detail in the above section(1). Thereby, the non-powder form freeze-dried composition can be madeinto a dry powdered preparation having a mean particle diameter of 10microns or less, preferably 5 microns or less or a fine particlefraction of 10% or more, preferably 20% or more, more preferably 25% ormore, still more preferably 30% or more, and in particular 35% or more.

As used herein, the mean particle diameter of fine particles indicates amean particle diameter usually adopted in the industry relating toinhalants. Specifically, the mean particle diameter is not a geometricmean particle diameter, but an aerodynamic mean particle diameter (massmedian aerodynamic diameter, MMAD) unless otherwise specified. Theaerodynamic mean particle diameter can be measured by a conventionalmethod. For example, the mass median aerodynamic diameter can bemeasured using a dry particle size distribution meter fitted with anAerobreather, which is an artificial lung model (manufactured by AmherstProcess Instrument, Inc., USA), a twin impinger (G. W. Hallworth and D.G. Westmoreland: J. Pharm. Pharmacol., 39, 966-972 (1987), U.S. Pat. No.6,153,224), a multi-stage liquid impinger, a Marple-Miller impactor, anAndersen cascade impactor or the like. Moreover, B. Olsson et al. havereported that delivery of the particles into the lungs increases at theproportion of particles having a mass median aerodynamic diameter of 5μm or less increases (B. Olsson et al.: Respiratory Drug Delivery V,273-281(1996)). The fine particle fraction, fine particle dose or thelike as measured by a twin impinger, a multi-stage liquid impinger, aMarple-Miller impactor, an Andersen cascade impactor or the like acts asa method of estimating the amount that can be delivered into the lungs.

The manufacturing method of the present invention can be implemented byfilling into a vessel the composition liquid containing ingredients inthe non-dissolved form, generating the non-powder form freeze-driedcomposition by freeze-drying the composition liquid in the non-dissolvedform, and applying the air impact defined in the above to the generatedfreeze-dried composition by introducing air into the vessel housing thegenerated composition. In this case, freeze-drying process and a processfor making a powder into a preparation can be carried out using the samevessel, which can avoid a loss or contamination resulting fromsubdividing.

The method of applying the air impact to the freeze-dried composition isnot limited; however, a dry powder inhaler which will be described inthe section (3) below is preferably used.

The method of manufacturing the dry powdered preparation fortranspulmonary administration of the present invention is alsocharacterized in that a patient administering the dry powderedpreparation can prepare by him/herself the powdered preparation fortranspulmonary administration at the time of use (inhalation) by makingthe freeze-dried composition housed in a vessel into fine particleshaving a particle diameter suitable for transpulmonary administration.

The method of manufacturing a dry powdered preparation of the presentinvention encompasses the specific embodiments defined in the followingitems:

201. A method of manufacturing a dry powdered preparation fortranspulmonary administration, comprising:

introducing air into a vessel to apply to a freeze-dried composition anair impact having an air speed of at least 1 m/sec and an air flow rateof at least 17 ml/sec using a device capable of applying said air impactto the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more;

the freeze-dried composition prepared by freeze-drying the compositionliquid containing ingredients in the non-dissolved form and having thefollowing properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof the air impact.

202. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein thefreeze-dried composition housed in the vessel containing a single doseof an active ingredient.

203. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein the fineparticles prepared have a mean particle diameter of 5 microns or less ora fine particle fraction of 20% or more.

204. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein thedisintegration index of the freeze-dried composition is in a range of0.05 to 1.5.

205. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein thefreeze-dried composition contains a low-molecular-weight drug as theactive ingredient.

206. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein thefreeze-dried composition contains a high-molecular-weight drug such as aprotein, a nucleic acid or the like as the active ingredient.

207. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein thefreeze-dried composition contains a nucleic acid with held in theholder.

208. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 205, wherein thefreeze-dried composition contains a low-molecular-weight drug as theactive ingredient, and at least one selected from the group consistingof amino acids, dipeptides, tripeptides, and saccharides as a carrier.

209. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 206, wherein thefreeze-dried composition contains a high-molecular-weight drug such asproteins, a nucleic acid or the like as the active ingredient, and atleast one selected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

210. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 208, wherein thefreeze-dried composition contains a low-molecular-weight drug as theactive ingredient, and at least one selected from the group consistingof hydrophobic amino acids, hydrophobic dipeptides, and hydrophobictripeptides as the carrier.

211. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 209, wherein thefreeze-dried composition contains a high-molecular-weight drug such asproteins, a nucleic acid or the like as the active ingredient, and atleast one selected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

212. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, wherein thefreeze-dried composition is a water-soluble composition.

213. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, being a method ofmaking the freeze-dried composition into fine particles in a vesselhaving a volume of 0.2 to 50 ml.

214. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, carried out byusing a device having a member capable of applying an air impact havingan air speed of at least 2 m/sec and an air flow rate of at least 17ml/sec to the freeze-dried composition in the vessel, and introducingair having the air impact into the vessel housing the freeze-driedcomposition.

215. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, carried out byusing a device having a member capable of applying an air impact havingan air speed in a range of 1 to 300 m/sec and an air flow rate of atleast 17 ml/sec to the freeze-dried composition in the vessel, andintroducing air having the air impact into the vessel housing thefreeze-dried composition.

216. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, carried out byusing a device having a member capable of applying an air impact havingan air speed of at least 1 m/sec and an air flow rate of at least 20ml/sec to the freeze-dried composition in the vessel, and introducingair having the air impact into the vessel housing the freeze-driedcomposition.

217. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, carried out byusing a device having a member capable of applying an air impact havingan air speed of at least 1 m/sec and an air flow rate in a range of 17ml/sec to 15 L/sec to the freeze-dried composition in the vessel, andintroducing air having the air impact into the vessel housing thefreeze-dried composition.

218. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, characterized bymaking the freeze-dried composition into fine particles using the drypowder inhaler of item 301 or 302 shown in the section of (3) Dry powderinhaler as the device.

219. The method of manufacturing a powdered preparation fortranspulmonary administration according to item 218, characterized bymaking the freeze-dried composition into fine particles using the drypowder inhaler according to item 309 shown in the section of (3) Drypowder inhaler as the device.

220. The method of manufacturing a powdered preparation fortranspulmonary administration according to item 218, being a method ofmanufacturing a dry powdered preparation in which the freeze-driedcomposition is made into fine particles using the dry powder inhaleraccording to item 301 shown in the section of (3) Dry powder inhaler,wherein the amount of air jetted into said vessel each time using thedry powder inhaler is 5 to 100 ml.

221. The method of manufacturing a powdered preparation fortranspulmonary administration according to item 417, being a method ofmanufacturing a dry powdered preparation in which the freeze-driedcomposition is made into fine particles using the dry powder inhaler ofitem 302 shown in the section of (3) Dry powder inhaler, wherein theflow rate of air inhalation from the inhalation port using the drypowder inhaler is 5 to 300 L/min.

222. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 201, comprising:

introducing air into a vessel to apply to a freeze-dried composition anair impact having an air speed in a range of 1 to 300 m/sec and an airflow rate in a range of 17 ml/sec to 15 L/sec using a device capable ofapplying said air impact to the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more;

the freeze-dried composition prepared by freeze-drying the compositionliquid containing ingredients in the non-dissolved form and having thefollowing properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.05 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof the air impact.

223. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 222, wherein thefreeze-dried composition housed in the vessel contains a single dose ofan active ingredient.

224. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 222, wherein the airspeed is 1 to 250 m/sec.

225. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 222, wherein the airflow rate is 20 ml/sec to 10 L/sec.

(3) Dry Powder Inhaler

The dry powder inhaler used suitably for manufacturing a dry powderedpreparation for transpulmonary administration of the present inventionis a device used for breaking down a freeze-dried preparation(freeze-dried composition) that has been housed in a non-powder form ina vessel into fine particles in the vessel, and further allowing a userto inhale the dry powdered preparation.

By comprising {circle around (1)} a member capable of applying an airimpact to the non-powder form freeze-dried composition in a degree suchthat the freeze-dried composition can be pulverized into fine particles,and {circle around (2)} a member capable of administering to a user byinhalation the powder-form freeze-dried composition that has been madeinto fine particles, the device can carry out both breaking down of thefreeze-dried composition into fine particles and administration of thepowdered composition to a user by inhalation. Note that the member{circle around (1)} can also appreciated as a member for introducing airhaving the above-mentioned air impact into the vessel housing thefreeze-dried composition. Moreover, the member {circle around (2)} canalso appreciated as a member for discharging out of the vessel thepowdered preparation that has been made into fine particles in thevessel. In a dry powder inhalation system of the present invention, aslong as the device comprises these members, either a conventionalpublicly-known device or a device which will be developed in the futurecan also be used.

Specifically, the member {circle around (1)} can be realized byintroducing air capable of applying an air impact as above into thevessel housing the freeze-dried composition. Note that the member{circle around (1)} can be altered into a member capable of applying anair impact having an air speed of at least 1 m/sec and an air flow rateof at least 17 ml/sec to the freeze-dried composition in the vessel. Byusing the member {circle around (2)} or via this member, the drypowdered preparation, which has been prepared into a form suitable fortranspulmonary administration, can be administered by inhalation to theuser such as patient. Note that, for example a chamber or a flow pathsuch that the composition is made into fine particles or scattered maybe further provided in the member {circle around (2)}.

The device in question encompasses jet type dry powder inhalers as in(a) below and self-inhaling type dry powder inhalers as in (b) below.

(a) Jet Type Dry Powder Inhaler: Active Powder Inhaler

(a-1) A dry powder inhaler used in the making into fine particles andinhalation of a freeze-dried composition that has been housed in anon-powder form in a vessel,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding member for feedingair into the air jet flow path of the needle part, and an inhalationport that communicates with the discharge flow path, and

being constituted such that a stopper that seals up the vessel ispierced by the needle parts, thus communicating the air jet flow pathand the discharge flow path with the inside of the vessel, and air isjetted into the vessel from the air jet flow path using the airpressure-feeding member, thus breaking down the freeze-dried compositioninto fine particles by the impact of the jetted air, and discharging thefine particles obtained out from the inhalation port via the dischargeflow path.

(a-2) The dry powder inhaler described in (a-1) above, being constitutedsuch that the air pressure-feeding member is manually operated andcomprises a bellows body having an intake port equipped with an intakevalve and a discharge port equipped with a discharge valve, and bycontracting the bellows body and thus opening the discharge valve in astate in which the intake valve is closed, air in the bellows body ispressure-fed into the vessel through the air jet flow path of the needlepart which communicates with the discharge port, and by expanding thebellows body through an elastic restoring force in a state in which thedischarge valve is closed and the intake valve is open, air isintroduced into the bellows body.

(a-3) The dry powder inhaler described in (a-1) or (a-2) above, in whichthe air jet flow path and the discharge flow path are formed in a singleneedle part.

(b) Self-Inhaling Type Dry Powder Inhaler: Passive Powder Inhaler

(b-1) A dry powder inhaler used for inhaling fine particles obtained bybreaking down a freeze-dried composition that has been housed in anon-powder form in a vessel,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with the suction flow path,

and being constituted such that, in a state in which a stopper thatseals up the vessel has been pierced by the needle parts, through theinhalation pressure of a user, air in the vessel is inhaled from theinhalation port, and at the same time outside air flows into the vessel,which is now at a negative pressure, through the air introduction flowpath, and as a result the freeze-dried composition is broken down intofine particles by the impact of the air flowing in, and the fineparticles obtained are discharged from the inhalation port through thesuction flow path.

(b-2) The dry powder inhaler described in (b-1) above, being constitutedsuch that most part of the freeze-dried composition is made into fineparticles and discharged from the inhalation port through one inhalationof the user.

(b-3) The dry powder inhaler described in (b-1) or (b-2) above, in whichthe suction flow path and the air introduction flow path are formed in asingle needle part.

The member for introducing air into the vessel (member {circle around(1)} mentioned above) may be a member for introducing air from theoutside at normal pressure. It is not necessary to use compressed airfrom a jet mill or the like. There are no limitations on the member forintroducing air from the outside. For example, in the case where the jettype dry powder inhaler (active powder inhaler) described above is used,a member for artificially introducing external air into the vessel byjetting can be employed. In the case where the self-inhaling type drypowder inhaler is used, a member for naturally introducing outside airinto the vessel by suction through negative pressure formed in thevessel when the user inhales can be employed. Moreover, in the formercase, i.e. in the jet type dry powder inhaler, the method of introducingexternal air into the vessel by jetting artificially may be manual ormay be a method that is carried out automatically using a machine.

The dry powder inhaler of the present invention, regardless of the typeof the inhaler, whether it is an active powder inhaler or a passivepowder inhaler, is capable of breaking down the freeze-dried compositionthat has been stored in non-powder form in the vessel into fineparticles using an impact (jet pressure) of external air introduced into(flowing into) the vessel by the air introduction member.

For example, a vessel, used for freeze-drying can be used here, with nolimitations on the material, shape etc. As the material, a plasticmainly including a polyolefin such as polyethylene, polypropylene orpolystyrene, glass, aluminum and the like can be given as examples.Moreover, as the shape, a circular cylinder, a cup shape, and apolygonal prism (polygonal pyramid) such as a triangular prism(triangular pyramid), a square prism (square pyramid), a hexagonal prism(hexagonal pyramid) or an octagonal prism (octagonal pyramid) can begiven as examples.

To obtain the effects efficiently, the volume of the vessel housing thefreeze-dried composition is in a range of 0.2 to 50 ml, preferably 0.2to 25 ml and more preferably 1 to 15 ml. Moreover, it is desirable to beused the trunk inside diameter of the vessel be 2 to 100 mm, preferably2 to 75 mm, more preferably 2 to 50 mm.

Moreover, the amount of the freeze-dried composition housed in thevessel is preferably an amount containing a unit dose (single dose) or aplurality of doses, specifically 2 to 3 doses, of the active ingredient.More preferably, it is an amount containing a unit dose (single dose) ofthe active ingredient. Moreover, the specific amount of the freeze-driedcomposition will vary according to the type and content of the activeingredient contained in the freeze-dried composition, and is selected asappropriate from amounts that can be inhaled, with there being noparticular limitation; nevertheless, the amount is generally 30 mg orless, preferably 20 mg or less, more preferable 10 mg or less,particularly preferably 5 mg or less.

Moreover, the air impact generated by the outside air introduced intothe vessel is stipulated through the air flow rate at which air flowsinto the vessel through at least one or a plurality of inhalations of aperson or the air speed thus generated. There is no particularlimitation on introducing external air with an air flow rate or airspeed greater than this, except of course that the durability of thevessel is a limitation. Generally the air flow rate for one inhalationof a person is 5 to 300 L/min, more specifically 10 to 200 L/min.Moreover, in the case of an dry powder inhaler, a device can be usedsuch that the amount of air jetted each time is 5 to 100 ml, preferably10 to 50 ml. Preferably, adjustment can be carried out such that an airimpact generated through an air speed of at least 1 m/sec is applied tothe surface of the freeze-dried composition filled in the vessel. A morepreferable air impact is an impact generated by an air speed of at least2 m/sec, a yet more preferable one is an impact generated by an airspeed of at least 5 m/sec, and a still more preferable one is an impactgenerated by an air speed of at least 10 m/sec. Here, there is noparticular limitation on the upper limit of the air impact, but animpact generated by an air speed of 300 m/sec can be given as anexample. The upper limit is preferably an impact generated through anair speed 250 m/sec, more preferably an impact generated through an airspeed 200 m/sec, yet more preferably an impact generated through an airspeed 150 m/sec.

There is no particular limitation on the air impact as long as it isgenerated by air having an air speed arbitrarily selected from the rangeextending from a lower limit to an upper limit. Specific examples areimpacts generated through an air speed in a range of 1 to 300 m/sec, 1to 250 m/sec, 2 to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200m/sec or 10 to 150 m/sec.

Here, the speed of the air applied to the freeze-dried composition canbe measured as follows. That is, with the jet type dry powder inhalershown later as Embodiment 1, a mechanism is adopted in which air storedin a bellows body 10 is forcibly introduced onto the freeze-driedcomposition (cake-like freeze-dried composition: hereinafter alsoreferred to as ‘freeze-dried cake’) that has been filled into the vesselfrom an air jet flow path 3, thus applying an air impact, anddischarging the resulting fine particles from a discharge flow path 4.In this case, the flow rate of the air flowing through the air jet flowpath 3 can be calculated by dividing the amount of air stored in thebellows body 10 by the time over which the air is fed into the vessel.Next, by dividing this air flow rate by the cross-sectional area of apath to introduce air into the vessel such as the air jet flow path 3,the air speed at which the impact is applied to the freeze-driedcomposition (freeze-dried cake) can be calculated.Airspeed (cm/sec)=air flow rate (ml=cm³/sec)+cross-sectional area of airintroduction flow path (cm²)

Specifically, in the case for example of a jet type dry powder inhalerdesigned such that the bore of the air jet flow path 3 is 1.2 mm, thebore of the discharge flow path is 1.8 mm, and the amount of air storedin the bellows body 10 is about 20 ml, in the case that the amount ofair of about 20 ml stored in the bellows body 10 is forcibly introducedonto the freeze-dried composition in the vessel from the air jet flowpath 3 in about 0.5 seconds, the air flow rate becomes about 40 ml/sec.Dividing this value by the cross-sectional area of the air introductionflow path (the air jet flow path) (0.06×0.06×3.14=0.0113 cm²), gives3,540 cm/sec. The air speed is thus about 35 m/sec.

Moreover, with the self-inhaling type dry powder inhalers shown later asEmbodiments 2, 3 and 4, a mechanism is adopted in which air flowing infrom an air introduction flow path 17 applies an impact to thefreeze-dried cake, and then the resulting fine particles are dischargedfrom a suction flow path 16; the bores of the air introduction flow path17 and the suction flow path 16 thus stipulate the flow rate of the airflowing through the paths. The air speed applied to the freeze-driedcomposition in the vessel can thus be calculated by measuring the flowrate of the air flowing through the air introduction flow path 17 anddividing this by the cross-sectional area of the air introduction flowpath 17.Airspeed (cm/sec)=air flow rate (ml=cm³/sec)+cross-sectional area of airintroduction flow path 17 (cm²)

Specifically, the flow rate of the air flowing through the airintroduction flow path 17 can be measured by installing the dry powderinhaler including the vessel in the slot part of apparatus A (a twinimpinger: manufactured by Copley, UK) as mentioned in the EuropeanPharmacopoeia (Third Edition Supplement 2001, p113-115), and using aflow meter (KOFLOC DPM-3).

For example, with a self-inhaling type dry powder inhaler designed suchthat the bore of the air introduction flow path 17 is 1.99 mm and thebore of the suction flow path is 1.99 mm, in the case that the air flowrate flowing through the air introduction flow path 17 measured usingthe flow meter (KOFLOC DPM-3) was 17.7 L/min, i.e. 295 ml/sec, the airspeed can be obtained by dividing this value by the cross-sectional areaof the air introduction flow path 17 (0.0995×0.0995×3.14=0.0311 cm²)(9,486 cm/sec, i.e. 95 m/sec).

Moreover, at least 17 ml/sec can be given as an example of the flow rateof the air applied to the freeze-dried composition filled in the vessel.The air flow rate is preferably at least 20 ml/sec, more preferably atleast 25 ml/sec. Here there is no particular limitation on the upperlimit of the air flow rate, but an example of 900 L/min can be given.This upper limit is preferably 15 L/sec, more preferably 10 L/sec, yetmore preferably 5 L/sec, still more preferably 4 L/sec, particularlypreferably 3 L/sec. Specifically, the flow rate should be in a rangeconstituted from a lower limit and an upper limit selected asappropriate from the above, with there being no particular limitation;nevertheless, 17 ml/sec to 15 L/sec, 20 ml/sec to 10 L/sec, 20 ml/sec to5 L/sec, 20 ml/sec to 4 L/sec, 20 ml/sec to 3 L/sec, and 25 ml/sec to 3L/sec, can be given as examples of the range.

Moreover, as a member for raising the impact pressure of the airintroduced from the outside, the dry powder inhaler used in the presentinvention can have a mamber for discharging air from a discharge port,as explained in detail below, preferably with a small bore, of a flowpath close to the freeze-dried composition housed at the bottom of thevessel, for example a needle part having an air introduction flow pathor an air jet flow path as described later in the embodiments. Regardingthe bore of the discharge port of the flow path, the preferable rangevaries according to the size of the vessel and so on, with there beingno particular limitations; nevertheless, the bore can be in a range of0.3 to 10 mm, preferably 0.5 to 5 mm, more preferably 0.8 to 5 mm, muchmore preferably 1 to 4 mm.

The freeze-dried composition housed in a non-powder form in the vesselcan be made into fine particles by introducing air into the vessel.Here, the extent of making into fine particles should be such that theparticle diameter is suitable for transpulmonary administration; aparticle diameter of 10 μm or less, preferably 5 μm or less, can begiven as an example.

The dry powder inhaler for use in the present invention encompasses thespecific embodiments defined in the following items:

300. A dry powder inhaler for transpulmonary administration used formaking a freeze-dried composition that has been housed in non-powderform in a vessel into fine particles by an air impact, and administeringthe resulting fine particles to a user by inhalation.

301. The dry powder inhaler for transpulmonary administration accordingto item 300, being a device used for making a freeze-dried compositionthat has been housed in non-powder form in a vessel into fine particles,and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding member for feedingair into the air jet flow path of said needle part, and an inhalationport that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding member, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path.

302. The dry powder inhaler for transpulmonary administration accordingto item 300, being a device used for pulverizing a freeze-driedcomposition that has been housed in non-powder form in a vessel intofine particles, and administering the resulting fine particles to a userby inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

303. The dry powder inhaler for transpulmonary administration accordingto item 301, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles anddischarged from said inhalation port through jetting air into saidvessel once.

304. The dry powder inhaler for transpulmonary administration accordingto item 301, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles, such thatthe mean particle diameter is 10 microns or less or the fine particlefraction is 10% or more, and discharged from said inhalation portthrough jetting air into said vessel.

305. The dry powder inhaler for transpulmonary administration accordingto item 301, wherein said air jet flow path and said discharge flow pathare formed in a single needle part.

306. The dry powder inhaler for transpulmonary administration accordingto item 302, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles anddischarged from said inhalation port through one inhalation of the user.

307. The dry powder inhaler for transpulmonary administration accordingto item 302, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles, such thatthe mean particle diameter is 10 microns or less or the fine particlefraction is 10% or more, and discharged from said inhalation portthrough inhalation of the user.

308. The dry powder inhaler for transpulmonary administration accordingto item 302, wherein said suction flow path and said air introductionflow path are formed in a single needle part.

309. The dry powder inhaler for transpulmonary administration accordingto item 308 comprising:

a holder part for holding a vessel that is sealed up with a stopper andhouses a freeze-dried composition in a non-powder cake-like form thatwill be made into fine particles upon receiving an air impact,

a member for applying an air impact to said freeze-dried composition insaid vessel, and sucking said freeze-dried composition in a powder-formthat has been made into fine particles by the air impact out from saidvessel,

a needle part having a suction flow path for sucking said freeze-driedcomposition out from said vessel, and an air introduction flow path forintroducing outside air into said vessel,

a suction port that communicates with said suction flow path of saidneedle part,

a guide part for guiding said holder part in the axial direction of saidneedle part,

a holder operating part that has a mechanism part for, when said vesselis held by said holder part, advancing the vessel towards a needle tipof said needle part to pierce the stopper of the vessel with said needletip, and retreating the vessel from said needle tip to separate thestopper of the vessel from said needle tip, and an operator thatoperates the mechanism part, and is constituted such that said operatingmember can be operated with a force smaller than the force necessary forthe mechanism part to pierce the stopper of the vessel with said needlepart,

and a housing that supports said needle part and is for providing saidsuction port, said guide part and said holder operating part,

and constituted such that, in a state in which said stopper has beenpierced by said needle part to communicate the suction flow path and theair introduction flow path of said needle part with the inside of saidvessel and position the tip of the air introduction flow path at saidfreeze-dried composition, through the inhalation pressure of a user, airin said vessel is inhaled from said suction port, and air is made toflow into said vessel through the air introduction flow path, thusapplying an air impact to the freeze-dried composition in said vessel.

310. The dry powder inhaler for transpulmonary administration accordingto item 309, characterized in that said housing is formed in a tubularshape, said suction port is formed at a tip part of the housing, ahousing chamber for housing said vessel via said holder is formed insaid housing, said needle part is disposed in said housing such thatsaid needle tip points towards said housing chamber, and an introductionport for introducing outside air that communicates with the airintroduction flow path of said needle part is provided in a wall of saidhousing,

and the dry powder inhaler is constituted such that said holder part isadvanced and retreated in the axial direction of said housing in saidhousing chamber using said holder operating part.

311. The dry powder inhaler for transpulmonary administration accordingto item 310, characterized in that said housing is formed from a housingmain body having a removal/insertion port for said vessel formed thereinin a position in which said holder part is retreated, and a lid for saidremoval/insertion port that is connected to said housing main body by ahinge,

and the dry powder inhaler is constituted such that said holderoperating part has said mechanism part which advances said holder parttowards the needle tip of the needle part when said lid is pushed downto close said removal/insertion port, and retreats said holder part awayfrom said needle tip when said lid is lifted up to open saidremoval/insertion port, and said lid is used as the operating member ofsaid mechanism part.

(4) Dry Powder Inhalation System for Transpulmonary Administration

The dry powder inhalation system for transpulmonary administration ofthe present invention is a system that combines a freeze-driedcomposition having a composition such that, by applying an air impact tothe freeze-dried composition which exists in a non-powder form havingbeen freeze-dried in a vessel and not subjected to processing such aspulverization, the freeze-dried composition can be made into fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more in the vessel, and a inhalingdevice comprising prescribed member. According to this dry powderinhalation system for transpulmonary administration, a user him/herselfcan prepare the freeze-dried composition which has been provided in anon-powder form into a powdered preparation comprising fine particleshaving a mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more, which is a preparation suitable fortranspulmonary administration, at the time of use (the time ofinhalation), and administer (take) the powdered preparation.

To obtain the effects of the dry powder inhalation system fortranspulmonary administration effectively, it is important to select thecomposition of the freeze-dried composition, the inhaling device, thevessel and so on appropriately.

It is preferable to use a freeze-dried composition which is prepared byfreeze-drying a composition liquid containing ingredients in thenon-dissolved form and is endowed with the following properties (i) to(iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec.

The detailed description of the composition and preparing method of thefreeze-dried composition of the present invention in the above section(1) holds for this section.

The freeze-dried composition is subjected to a freeze-drying process inthe vessel and it is to be housed therein. The amount of thefreeze-dried composition housed in the vessel is preferably an amountcontaining a unit dose (single dose) or a plurality of doses,specifically 2 to 3 doses, of the active ingredients. More preferably,it is an amount containing a unit dose (single dose) of the activeingredient. Moreover, the specific amount of the freeze-driedcomposition to be housed in the vessel will vary according to the typeand content of the active ingredient contained in the freeze-driedcomposition, and is selected as appropriate from amounts that can beinhaled, with there being no particular limitation; nevertheless, theamount is generally 30 mg or less, preferably 20 mg or less, morepreferably 10 mg or less, particularly preferably 5 mg or less.

As the dry powder inhaler, it is preferable to adopt a device comprising{circle around (1)} a member for applying an air impact (or a member forintroducing air) and {circle around (2)} a member for discharging fineparticles (or a member for administering by inhalation), in which, by amember for introducing air (member {circle around (1)}) air isintroduced into (inflow) a vessel which houses the non-powder-formfreeze-dried composition and the freeze-dried composition is pulverizedinto fine particles using the impact (jet pressure) of the air that hasbeen introduced into (flowed into) the vessel, and then, using themember {circle around (2)} for discharging fine particles, the driedpowder composition made into fine particles by the member {circle around(1)} is discharged from the vessel. Then, the fine particles aredirectly administered to a user.

An example of such device is the dry powder inhaler of the presentinvention mentioned in the section (3).

The dry powder inhalation system suitable for transpulmonaryadministration according to the present invention includes a vesselhousing the freeze-dried composition of the present invention and a drypowder inhaler of the present invention used in combination at the timeof inhalation. In other words, the dry powder inhalation system of thepresent invention, at least when used for inhalation, comprises thevessel housing the freeze-dried composition of the present invention andthe dry powder inhaler of the present invention.

According to the system of the present invention, by introducing airinto the vessel housing the freeze-dried composition of the presentinvention using the dry powder inhaler for applying an air impact havingan air speed of at least 1 m/sec and an air flow rate of at least 17ml/sec to the freeze-dried composition in the vessel. Thus, a drypowdered preparation having a particle size suitable for transpulmonaryadministration by inhalation or having fine particle fraction usableefficiently for transpulmonary administration by inhalation can beobtained.

Examples of the particle diameter suitable for transpulmonaryadministration by inhalation include the mean particle diameter, morespecifically, an aerodynamic mean particle diameter (mass medianaerodynamic diameter, MMAD) is 10 microns or less, preferably 5 micronsor less. The effective particle proportion (fine particle fraction) usedefficiently for transpulmonary administration by inhalation is at least10%, preferably at least 20%, more preferably 25%, yet more preferablyat least 30%, and in particular preferably at least 35%.

Furthermore, the system allows transpulmonary administration of theobtained dry powdered preparation directly to a user by inhalation.Therefore, the dry powder inhalation system for transpulmonaryadministration of the present invention is a system for producing a drypowdered preparation suitable for transpulmonary administration and, atthe same time, a system for transpulmonarily administering the drypowder preparation to a user.

The dry powder inhalation system for transpulmonary administration ofthe present invention encompasses the specific embodiments defined inthe following items:

401. A dry powder inhalation system for transpulmonary administration,using a combination of:

(1) a vessel housing a freeze-dried composition that is prepared byfreeze-drying a composition liquid containing ingredients in thenon-dissolved form and has the following properties:

(i) a non-powder cake-like form,

(ii) a disintegration index of 0.05 or more, and

(iii) a property of becoming fine particles having a mean particlediameter of 10 microns or less or a fine particle fraction of 10% ormore upon receiving an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec; and

(2) a device comprising a member capable of applying said air impact tothe freeze-dried composition in said vessel, and a member fordischarging the powder-form freeze-dried composition that has been madeinto fine particles.

402. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the vessel housing the freeze-driedcomposition contains active ingredients of a single dose.

403. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the vessel and the device are used incombination at the time of inhalation.

404. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the disintegration index of thefreeze-dried composition is in a range of 0.05 to 1.5.

405. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the air impact of (iii) is generated byair having an air speed of at least 2 m/sec and an air flow rate of atleast 17 ml/sec.

406. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the air impact of (iii) is generated byair having an air speed in a range of 1 to 300 m/sec and an air flowrate of at least 17 ml/sec.

407. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the air impact of (iii) is generated byair having an air speed of at least 1 m/sec and an air flow rate of atleast 20 ml/sec.

408. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the air impact of (iii) is generated byair having an air speed of at least 1 m/sec and an air flow rate in arange of 17 ml/sec to 15 L/sec.

409. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the freeze-dried composition has aproperty of becoming fine particles having a mean particle diameter of 5microns or less or a fine particle fraction of 20% or more upon receiptof an air impact.

410. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the freeze-dried composition contains alow-molecular-weight drug as the active ingredient.

411. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as proteins, a nucleic acid or the likeas the active ingredient.

412. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the freeze-dried composition contains anucleic acid as an active ingredient with held in the holder.

413. The dry powder inhalation system for transpulmonary administrationaccording to item 310, wherein the freeze-dried composition contains alow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

414. The dry powder inhalation system for transpulmonary administrationaccording to item 411, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as proteins, a nucleic acid or the likeas the active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

415. The dry powder inhalation system for transpulmonary administrationaccording to item 413, wherein the freeze-dried composition contains alow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

416. The dry powder inhalation system for transpulmonary administrationaccording to item 414, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as proteins, a nucleic acid or the likeas the active ingredient, and at least one selected from the groupconsisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

417. The dry powder inhalation system for transpulmonary administrationaccording to item 401, wherein the freeze-dried composition is awater-soluble composition.

418. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the device is:

i) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding member for feedingair into the air jet flow path of said needle part, and an inhalationport that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding member, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path, or

ii) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

419. The dry powder inhalation system for transpulmonary administrationaccording to item 418, as the device, using the dry powder inhalercomprising:

a holder part for holding a vessel that is sealed up with a stopper andhouses a freeze-dried composition in a non-powder cake-like form thatwill be made into fine particles upon receiving an air impact,

a member for applying an air impact to said freeze-dried composition insaid vessel, and sucking said freeze-dried composition in a powder-formthat has been made into fine particles by the air impact out from saidvessel,

a needle part having a suction flow path for sucking said freeze-driedcomposition out from said vessel, and an air introduction flow path forintroducing outside air into said vessel,

a suction port that communicates with said suction flow path of saidneedle part,

a guide part for guiding said holder part in the axial direction of saidneedle part,

a holder operating part that has a mechanism part for, when said vesselis held by said holder part, advancing the vessel towards a needle tipof said needle part to pierce the stopper of the vessel with said needletip, and retreating the vessel from said needle tip to separate thestopper of the vessel from said needle tip, and an operator thatoperates the mechanism part, and is constituted such that said operatingmember can be operated with a force smaller than the force necessary forthe mechanism part to pierce the stopper of the vessel with said needlepart,

and a housing that supports said needle part and is for providing saidsuction port, said guide part and said holder operating part,

and constituted such that, in a state in which said stopper has beenpierced by said needle part to communicate the suction flow path and theair introduction flow path of said needle part with the inside of saidvessel and position the tip of the air introduction flow path at saidfreeze-dried composition, through the inhalation pressure of a user, airin said vessel is inhaled from said suction port, and air is made toflow into said vessel through the air introduction flow path, thusapplying an air impact to the freeze-dried composition in said vessel.

420. The dry powder inhalation system for transpulmonary administrationaccording to item 401, using a combination of:

(1) a vessel housing a freeze-dried composition that is prepared byfreeze-drying a composition liquid containing ingredients in thenon-dissolved form, and has the following properties:

(i) a non-powder cake-like form,

(ii) a disintegration index in a range of 0.05 to 1.5, and

(iii) a property of becoming fine particles having a mean particlediameter of 10 microns or less or a fine particle fraction of 10% ormore upon receipt of an air impact having an air speed in a range of 1to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec;and

(2) a device comprising a member capable of applying said air impact tothe freeze-dried composition in said vessel, and a member fordischarging the powder-form freeze-dried composition that has been madeinto fine particles.

421. The dry powder inhalation system for transpulmonary administrationaccording to item 420, wherein the vessel housing the freeze-driedcomposition housing a freeze-dried composition containing a single doseof active ingredient.

422. The dry powder inhalation system for transpulmonary administrationaccording to item 420, wherein the air speed is 1 to 250 m/sec.

423. The dry powder inhalation system for transpulmonary administrationaccording to item 420, wherein the air flow rate is 20 ml/sec to 10L/sec.

(5) Transpulmonary Administration Method

The present invention further provides a transpulmonary administrationmethod comprising making a freeze-dried composition in a non-powder forminto fine particles suitable for transpulmonary administration at thetime of usage (administration), and administering the resultingpreparation in a powder form with fine particles by inhalation. Thetranspulmonary administration method can be carried out using the drypowder inhalation system for transpulmonary administration of thepresent invention described in detail in the section (4), and preferablyusing the dry powder inhalation system for transpulmonary administrationcomprising the vessel which houses the freeze-dried composition of thepresent invention described in detail in the section (1), which isprepared by freeze-drying the composition liquid containing ingredientsin the non-dissolved form and a dry powder inhaler described in thesection (3).

The transpulmonary administration method of the present inventionencompasses the specific embodiments defined in the following items:

501. A transpulmonary administration method comprising:

making a freeze-dried composition into fine particles having a meanparticle diameter of 10 microns or less or a fine particle fraction of10% or more by applying an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec to the freeze-driedcomposition at the time of use, and

administering the resulting fine particle powder to a user byinhalation;

the freeze-dried composition prepared by freeze-drying a compositionliquid containing ingredients in the non-dissolved form and having thefollowing properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof the air impact.

502. The transpulmonary administration method according to item 501,wherein the freeze-dried composition contains a single dose of activeingredients.

503. The transpulmonary administration method according to item 501,wherein the freeze-dried composition is housed in a vessel, and the fineparticle powder are made using a device comprising a member capable ofapplying the air impact to the freeze-dried composition in the vesseland a member for discharging the resulting fine particle powder-formfreeze-dried composition out of the vessel.

504. The transpulmonary administration method according to item 503,wherein the disintegration index of the freeze-dried composition is inthe range of 0.05 to 1.5.

505. The transpulmonary administration method according to item 503,wherein the air impact of (iii) is generated by air having an air speedof at least 2 m/sec and an air flow rate of at least 17 ml/sec.

506. The transpulmonary administration method according to item 503,wherein the air impact of (iii) is generated by air having an air speedin a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

507. The transpulmonary administration method according to item 503,wherein the air impact of (iii) is generated by air having an air speedof at least 1 m/sec and an air flow rate of at least 20 ml/sec.

508. The transpulmonary administration method according to item 503,wherein the air impact of (iii) is generated by air having an air speedof at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15L/sec.

509. The transpulmonary administration method according to item 503,wherein the freeze-dried composition contains a low-molecular-weightdrug as the active ingredient.

510. The transpulmonary administration method according to item 503,wherein the freeze-dried composition contains a high-molecular-weightdrug such as a protein, a nucleic acid or the like as the activeingredient.

511. The transpulmonary administration method according to item 503,wherein the freeze-dried composition contains a nucleic acid as theactive ingredient with held in the holder.

512. The transpulmonary administration method according to item 509,wherein the freeze-dried composition contains a low-molecular-weightdrug as the active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

513. The transpulmonary administration method according to item 510,wherein the freeze-dried composition contains a high-molecular-weightdrug such as proteins, a nucleic acid or the like as the activeingredient, and at least one selected from the group consisting of aminoacids, dipeptides, tripeptides, and saccharides as a carrier.

514. The transpulmonary administration method according to item 512,wherein the freeze-dried composition contains a low-molecular-weightdrug as the active ingredient, and at least one selected from the groupconsisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

515. The transpulmonary administration method according to item 513,wherein the freeze-dried composition contains a high-molecular-weightdrug such as proteins, a nucleic acid or the like as the activeingredient, and at least one selected from the group consisting ofhydrophobic amino acids, hydrophobic dipeptides, and hydrophobictripeptides as the carrier.

516. The transpulmonary administration method according to item 503,wherein the freeze-dried composition is a water-soluble composition.

517. The transpulmonary administration method according to item 503,being a method of making into fine particles and administering such thatthe fine particles have a mean particle diameter of 5 microns or less ora fine particle fraction of 20% or more.

518. The transpulmonary administration method according to item 503,using the dry powder inhaler of item 301 or 302 shown in the section of(1) Dry powder inhaler as the device.

519. The transpulmonary administration method according to item 518,using the dry powder inhaler of item 309 shown in the section of (3) Drypowder inhaler as the device.

520. The transpulmonary administration method according to item 503,wherein the freeze-dried composition has the following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.05 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed in a range of 1 to 300 m/secand an air flow rate in a range of 17 ml/sec to 15 L/sec,

and the fine particles are made using a dry powder inhaler comprising amember capable of applying said air impact to the freeze-driedcomposition in the vessel and a member for discharging the resultingfine particle powder-form freeze-dried composition out of the vessel.

521. The transpulmonary administration method according to item 520,wherein the air speed is 1 to 250 m/sec.

522. The transpulmonary administration method according to item 520,wherein the air flow rate is 20 ml/sec to 10 L/sec.

(6) Use of a Freeze-Dried Composition for Transpulmonary Administrationby Inhalation

The present invention also provides use of a freeze-dried composition ina non-powder form for the transpulmonary administration by inhalation.The use encompasses the specific embodiments defined in the followingitems:

601. Use of a freeze-dried composition for transpulmonary administrationby inhalation,

the freeze-dried composition prepared by freeze-drying a compositionliquid containing ingredients in the non-dissolved form and having thefollowing properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec, and being used by forming into fineparticles having said mean particle diameter or said fine particlefraction.

602. The use of a freeze-dried composition for transpulmonaryadministration according to item 601, wherein the freeze-driedcomposition contains the active ingredient of a single dose.

603. The use of a freeze-dried composition for transpulmonaryadministration according to item 601, wherein the freeze-driedcomposition is housed in a vessel, and the fine particles are made usinga device comprising a member capable of applying the air impact to thefreeze-dried composition in the vessel and a member for discharging theresulting fine particle powder-form freeze-dried composition out of thevessel.

604. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the disintegration indexof the freeze-dried composition is in the range of 0.05 to 1.5.

605. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed of at least 2 m/sec and anair flow rate of at least 17 ml/sec.

606. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed in a range of 1 to 300 m/secand an air flow rate of at least 17 ml/sec.

607. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed of at least 1 m/sec and anair flow rate of at least 20 ml/sec.

608. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed of at least 1 m/sec and anair flow rate in a range of 17 ml/sec to 15 L/sec.

609. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 5microns or less or a fine particle fraction of 20% or more uponreceiving an air impact.

610. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition contains a low-molecular-weight drug as the activeingredient.

611. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition contains a high-molecular-weight drug such as proteins, anucleic acid or the like as the active ingredient.

612. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition contains a nucleic acid as the active ingredient with heldin the holder.

613. The use of a freeze-dried composition for transpulmonaryadministration according to item 610, wherein the freeze-driedcomposition contains a low-molecular-weight drug as the activeingredient, and at least one selected from the group consisting of aminoacids, dipeptides, tripeptides, and saccharides as a carrier.

614. The use of a freeze-dried composition for transpulmonaryadministration according to item 611, wherein the freeze-driedcomposition contains a high-molecular-weight drug such as a protein, anucleic acid or the like as the active ingredient, and at least oneselected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

615. The use of a freeze-dried composition for transpulmonaryadministration according to item 613, wherein the freeze-driedcomposition contains a low-molecular-weight drug as the activeingredient, and at least one selected from the group consisting ofhydrophobic amino acids, hydrophobic dipeptides, and hydrophobictripeptides as the carrier.

616. The use of a freeze-dried composition for transpulmonaryadministration according to item 614, wherein the freeze-driedcomposition contains a high-molecular-weight drug such as proteins, anucleic acid or the like as the active ingredient, and at least oneselected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

617. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition is a water-soluble composition.

618. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, using the dry powder inhaler ofitem 301 or 302 shown in the section of (3) Dry powder inhaler as thedevice.

619. The use of a freeze-dried composition for transpulmonaryadministration according to item 618, using the dry powder inhaler ofitem 109 shown in the section of (3) Dry powder inhaler as the device.

620. The use of a freeze-dried composition for transpulmonaryadministration according to item 603, wherein the freeze-driedcomposition which is prepared by freeze-drying a composition liquidcontaining ingredients in the non-dissolved form and has the followingproperties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.05 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed in a range of 1 to 300 m/sec and anair flow rate in a range of 17 ml/sec to 15 L/sec,

and the fine particles are made using a device comprising a membercapable of applying the air impact to the freeze-dried composition inthe vessel and a member for discharging the resulting fine particlepowder-form freeze-dried composition out of the vessel.

621. The use of a freeze-dried composition in transpulmonaryadministration according to item 620, wherein the air speed is 1 to 250m/sec.

622. The use of a freeze-dried composition in transpulmonaryadministration according to item 620, wherein the air flow rate is 20ml/sec to 10 L/sec.

(7) Use of a Freeze-Dried Composition for Manufacture of a Dry PowderedPreparation for Transpulmonary Administration by Inhalation

Furthermore, the present invention provides use of a freeze-driedcomposition in a non-powder form for manufacture of a dry powderedpreparation for transpulmonary administration by inhalation. The useencompasses the specific embodiments defined in the following items:

Use of a freeze-dried composition for manufacture of a dry powderedpreparation for transpulmonary administration by inhalation,

the freeze-dried composition having the following properties:

(i) prepared by freeze-drying a composition liquid containingingredients in the non-dissolved form,

(ii) has a non-powder cake-like form,

(iii) has a disintegration index of 0.05 or more, and

(iv) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec, and being used by forming into fineparticles having said mean particle diameter or said fine particlefraction at the time of use.

702. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains the active ingredientof a single dose.

703. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the disintegration index of the freeze-dried composition isin the range of 0.05 to 1.5.

704. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

705. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed in a range of 1 to 300 m/sec and an air flow rate of at least 17ml/sec.

706. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

707. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate in a range of 17 ml/secto 15 L/sec.

708. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 5 microns or less or a fine particlefraction of 20% or more upon receipt of an air impact.

709. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains alow-molecular-weight drug as an active ingredient.

710. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as proteins, a nucleic acid or the likeas an active ingredient.

711. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains a nucleic acid as theactive ingredient with held in the holder.

712. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains alow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

713. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item710, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as proteins, a nucleic acid or the likeas the active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

714. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item712, wherein the freeze-dried composition contains alow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

715. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item713, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as proteins, a nucleic acid or the likeas the active ingredient, and at least one selected from the groupconsisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

716. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition is a water-solublecomposition.

717. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the mean particle diameter of the fine particles of thepowdered preparation for transpulmonary administration is 5 microns orless or the fine particle fraction of the fine particles is 20% or more.

718. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition is housed in a vessel, and thefine particles are prepared by using a device comprising a member forapplying a prescribed air impact to the freeze-dried composition housedin the vessel and a member for discharging the resulting fine particlepowder form freeze-dried composition out of the vessel.

719. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration of item 718,using the dry powder inhaler according to item 301 or 302 shown in thesection of (3) Dry powder inhaler as the device.

720. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item719, using the dry powder inhaler of item 309 shown in the section of(3) Dry powder inhaler as the device.

721. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, using the freeze-dried composition having the following properties:

(i) prepared by freeze-drying a composition liquid containingingredients in the non-dissolved form,

(ii) has a non-powder cake-like form,

(iii) has a disintegration index in a range of 0.05 to 1.5, and

(iv) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed in a range of 1 to 300 m/secand an air flow rate in a range of 17 ml/sec to 15 L/sec.

722. The use of a freeze-dried composition for manufacture of a powderedpreparation for transpulmonary administration according to item 721,wherein the air speed is 1 to 250 m/sec.

723. The use of a freeze-dried composition for manufacture of a powderedpreparation for transpulmonary administration according to item 721,wherein the air flow rate is 20 ml/sec to 10 L/sec.

(8) Use of a Composition Liquid Containing Ingredients in theNon-Dissolved Form for Manufacture of a Freeze-Dried PowderedComposition for Preparing a Dry Powder Preparation for TranspulmonaryAdministration

Furthermore, the present invention relates to a use of a compositionliquid containing ingredients in the non-dissolved form for manufactureof a freeze-dried powdered composition for preparing a dry powderpreparation for transpulmonary administration.

It should be noted that the composition in the non-dissolved formcontaining ingredients for manufacture of a freeze-dried composition, apreparation method thereof, a preparation method of a freeze-driedcomposition using the same, a method of using the freeze-driedcomposition obtained (a preparation method of a freeze-dried preparationfor transpulmonary administration) are as described in the above.

EXAMPLE

Following is a detailed description of the present invention, citingexamples; however, the present invention is not limited to theseexamples.

In the following examples, the disintegration index of thenon-powder-form freeze-dried composition (freeze-dried cake) of thepresent invention, and the fine particle fraction (%), which is anindicator for evaluating the delivery into the lungs of the dry powderedpreparation produced, were calculated in accordance with the followingmethods.

<Calculation of Disintegration Index>

1.0 ml of n-hexane is instilled gently down the wall of the vessel intothe prepared non-powder-form freeze-dried composition (freeze-driedcake), and agitation is carried out for about 10 seconds at 3,000 rpmusing an Automatic Lab-Mixer NS-8 (manufactured by Pasolina). Themixture obtained is put into a UV cell (manufactured by Shimadzu GLCCenter) of optical path length 1 mm and optical path width 10 mm, andthen the turbidity of the mixture is measured immediately at ameasurement wavelength of 500 nm using a spectrophotometer (UV-240,manufactured by Shimadzu Corporation). The value obtained by dividingthe turbidity obtained by the total formulation amount (the total amount(weight) of the active ingredient and the carrier) is taken as thedisintegration index.

<Calculation of Fine Particle Fraction>

A vessel filled with the prepared non-powder-form freeze-driedcomposition is installed into the dry powder inhaler, and using thedevice a prescribed air impact is applied on the composition, and thefine powdered preparation thus produced is discharged directly intoapparatus A (a twin impinger: manufactured by Copley, UK) as mentionedin the European Pharmacopoeia (Third Edition Supplement 2001, p113-115).After this, the solvents in stage 1 and stage 2 of the apparatus arerespectively collected, and the active ingredient contained in eachsolvent in the stage 1 or stage 2 is assayed using an appropriate methodin accordance with the type of active ingredient in the freeze-driedcomposition, for example a bioassay method or HPLC (see the report ofLucas et al. (Pharm. Res., 15 (4), 562-569 (1998)) and the report ofIida et al. (Yakugaku Zasshi, 119 (10), 752-762 (1999)). The fractionthat can be expected to be delivered into the lungs is that in stage 2(the aerodynamic diameter of particles recovered in this fraction is 6.4μm or less); the proportion of the active ingredient that reaches stage2 and is recovered here is generally called the fine particle fraction(the amount that can be expected to reach the lungs), and is taken as ayardstick for evaluating the suitability as an inhalation fortranspulmonary administration.

In the Examples and Comparative Examples given below, the activeingredients contained in stage 1 and stage 2 were quantitated, and theweight amount of the active ingredient in stage 2 was divided by thetotal weight amount of the active ingredients jetted out (the totalweight amount of the active ingredients contained in stage 1 and stage2: hereinafter also referred to as “Stage 1+Stage 2”) to calculate fineparticles fraction. Moreover, as a rule in the European Pharmacopoeia,when using the twin impinger (manufactured by Copley, UK), it isstipulated that suction is carried out at an air suction flow rate of 60L/min, i.e. 1 L/sec, and hence in the Examples and Comparative Examplesbelow this was followed.

Embodiment 1 Dry Powder Inhaler (Jet Type 1)

A description of an embodiment of the jet type dry powder inhaler usedin the present invention will now be given using FIG. 1.

The dry powder inhaler is an air jet type apparatus for breaking downinto fine particles and delivering into the lungs a unit or a pluralityof doses of a non-powder-form freeze-dried composition 2 housed at thebottom of a vessel 1, and comprises a needle 5 that has an air jet flowpath 3 and a discharge flow path 4, an air intake member 7 that has aninhalation port 6 and is attached to a base end of the needle part 5, atubular safety cover 8 that surrounds the needle part 5 and also holdsthe vessel 1, and air pressure-feeding member 9.

The air pressure-feeding member 9 is manually operated and comprises atubular bellows body 10. An intake port 12 equipped with an intake valve11, and a discharge port 14 equipped with a discharge valve 13 areprovided in the bellows body 10. The discharge port 14 is attached to aconnecting port 15 formed at the base end of the air jet flow path 3 ofthe needle part 5, and communicates with the air jet flow path 3. Byapplying a compressive force to the bellows body 10 and thus contractingthe bellows body 10 in a state in which the intake valve 11 is closed,the discharge valve 13 is opened, and air in the bellows body 10 isdischarged into the vessel 1 from the discharge port 14 via the air jetflow path 3. When the compressive force is released, on the other hand,the bellows body 10 expands due to the elastic restoring force of thebellows body 10, and in a state in which the discharge valve 13 isclosed, the intake valve 11 opens, and air is introduced into thebellows body 10.

When using the dry powder inhaler, as shown in FIG. 1, the vessel 1 isinserted into the tubular safety cover 8, and a stopper 1 a of thevessel 1 is pierced by the needle part 5, thus communicating the air jetflow path 3 and the discharge flow path 4 with the inside of the vessel1. In this state, if the bellows body 10 of the air pressure-feedingmember 9 is contracted to discharge air from the discharge port 14, thenthis air passes through the air jet flow path 3 and is jetted out fromthe tip of the needle part 5 towards the freeze-dried composition 2 inthe vessel, and due to the resulting air impact the freeze-driedcomposition 2 becomes fine particles, which then pass through thedischarge flow path 4 of the needle part 5 and are discharged from theinhalation port 6 of the air intake member 7. The user (patient) inhalesthese fine particles from the inhalation port 6 of the air intakemember, whereupon the fine particles of the freeze-dried composition 2are delivered into the lungs of the user (patient). The material of thestopper of the vessel for use in the invention is not limited, and canbe selected from materials usually used for a stopper of a vessel forholding a drug or compound, such as rubber, plastic, aluminum or thelike.

With this jet type dry powder inhaler, the air jet amount is set to beabout 20 ml, the volume of the vessel about 5 ml, the bore (diameter) ofthe air jet flow path 3 about 1.2 mm, and the bore (diameter) of thedischarge flow path 4 about 1.8 mm.

Note, however, that there is no limitation to this. The preferable rangefor the bores of the air jet flow path 3 and the discharge flow path 4varies according to the size of the vessel and so on. These bores can beselected as appropriate from a range of 0.3 to 10 mm, preferably 0.3 to7 mm, more preferably 0.5 to 5 mm.

Moreover, regarding the air pressure-feeding member 9, the dischargeamount of fine particles required for administration by inhalation canbe adjusted by adjusting the speed of compression of the bellows body10. Adjustment can also be carried out by such air jet such that most ofthe freeze-dried composition 2 is broken down into fine particles.

Embodiment 2 Dry Powder Inhaler (Self-Inhaling Type 1)

A description of an embodiment (first embodiment) of the self-inhalingtype dry powder inhaler used in the present invention will now be givenusing FIG. 2. The dry powder inhaler shown in FIG. 2 comprises a needlepart 5 having a suction flow path 16 and an air introduction flow path17, a tubular safety cover 8, and an air intake member 19 that has aninhalation port 18 and communicates with the suction flow path 16. Theair intake member 19 is connected to the base end of the suction flowpath 16 of the needle part 5.

When using the dry powder inhaler, as shown in FIG. 2, the vessel 1 isinserted into the tubular safety cover 8, and an stopper 1 a of thevessel 1 is pierced by the needle part 5, thus communicating the suctionflow path 16 and the air introduction flow path 17 with the inside ofthe vessel 1. In this state, through the inhalation pressure of the user(patient), air in the vessel 1 is sucked in from the inhalation port 18via the suction flow path 16, and at the same time outside air flowsinto the vessel 1, which is now at a negative pressure, from the airintroduction flow path 17. At this time, the freeze-dried composition 2is made into fine particles through the air impact acting on thefreeze-dried composition 2, and the fine particles produced aredelivered into the user's (patient's) lungs from the inhalation port 18via the suction flow path 16.

Moreover, with this dry powder inhaler, setting is carried out such thatmost of the freeze-dried composition 2 is made into fine particles anddischarged from the inhalation port 18 through one inhalation of theuser (patient). It is considered that the air flow rate of oneinhalation of the user (patient) is 5 to 300 L/min, preferably 10 to 200L/min, more preferably 10 to 100 L/min, but the design of theself-inhaling type dry powder inhaler of the present invention ismodified as appropriate in accordance with the respiratory ability ofthe user (patient) using the device. With the dry powder inhaler shownin FIG. 2, in accordance with the respiratory ability of the user(patient) in question, the volume of the vessel has been set to about 10ml, and the bores of the air introduction flow path 17 and the suctionflow path 16 to about 1.5 mm. As a result, the settings are such thatthe freeze-dried composition 2 is made into fine particles anddischarged from the inhalation port 18 with virtually none left behindthrough one inhalation of the user (patient).

Embodiment 3 Dry Powder Inhaler (Self-Inhaling Type 2)

A description of an embodiment (second embodiment) of the self-inhalingtype dry powder inhaler used in the present invention will now be givenusing FIG. 3. The dry powder inhaler shown in FIG. 3 is the same as thejet type dry powder inhaler shown in FIG. 1 with the bellows body 10used for pressure-feeding air removed from the connecting port 15. Thedischarge flow path 4 of the jet type dry powder inhaler of FIG. 1corresponds to a suction flow path 16, the air jet flow path 3 to an airintroduction flow path 17, and the air intake member 7 having theinhalation port 6 to an air intake member 19 having an inhalation port18.

When using the self-inhaling type dry powder inhaler in question, themain points are the same as with the dry powder inhaler shown in FIG. 2.Through the inhalation pressure of the user (patient), air in the vessel1 is sucked in from the inhalation port 18 via the suction flow path 16,and at the same time outside air flows into the vessel 1, which is nowat a negative pressure, from the air introduction flow path 17. Thefreeze-dried composition 2 is made into fine particles through the airimpact produced accompanying this inflow of air. The fine particlesproduced are then delivered into the user (patient's) lungs from theinhalation port 18. As mentioned before, the air flow rate for oneinhalation of the user (patient) is generally in a range of 5 to 300L/minute; however, with the dry powder inhaler shown in FIG. 3, inaccordance with the respiratory ability of the user (patient) inquestion, the volume of the vessel was set to about 5 ml, the bore(diameter) of the air introduction flow path 17 to about 1.2 mm, and thebore (diameter) of the suction flow path 16 to about 1.8 mm. As aresult, the settings are such that most of the freeze-dried composition2 is made into fine particles and discharged from the inhalation port 18through one inhalation of the user (patient).

If the self-inhaling type dry powder inhaler is constituted in this way,then by detachably installing air pressure-feeding member 9 such as abellows body 10 into the connecting port 15, the self-inhaling type drypowder inhaler can be changed into a jet type. A single dry powderinhaler can thus be used as either a self-inhaling type or a jet type asdesired.

Each of the above dry powder inhalers of the present invention,regardless of whether it is a self-inhaling type or a jet type, can beconstituted such that it is possible to select and set the size of theair impact such that the freeze-dried composition becomes fine particlesof mean particle diameter 10 microns or less, preferably 5 microns orless, and flies out with almost none left behind.

Embodiment 4 Dry Powder Inhaler (Self-Inhaling Type 3)

A description of an embodiment (third embodiment) of the self-inhalingtype dry powder inhaler used in the present invention will now be givenusing FIGS. 4 to 10. FIG. 4 is a perspective view showing the dry powderinhaler, and FIG. 5 is a cross section showing the dry powder inhaler.Moreover, FIG. 6(a) is a partial cross section showing a needle part 5and a suction port 31 of the dry powder inhaler, and (b) is a side viewof the needle part 5. Furthermore, FIGS. 7 to 10 are cross sections forexplaining the operation of the dry powder inhaler.

The dry powder inhaler comprises a needle part 5 in which are formed asuction flow path 16 and an air introduction flow path 17, a holder part22 for holding a vessel 1, a housing chamber 20 for housing the vessel 1via the holder part 22, a guide part 23 provided in the housing chamber20 for guiding the holder part 22 in the axial direction of the needlepart 5, and a holder operating part 24 for advancing and retreating theholder part 22 along the guide part 23; these are all housed in atubular housing 21. Moreover, a mouthpiece 32 that has a suction port 31and communicates with the suction flow path 16 of the needle part 5 isprovided at a tip of the housing 21.

As shown in FIG. 7, in detail the housing 21 is formed from a housingmain body 26 in which is formed a removal/insertion port 25 in aposition in which the holder part 22 is retreated, and a lid 27 thatopens and closes the removal/insertion port 25. The lid 27 is connectedto the housing main body 26 by a hinge 21A, and a window 28 forverifying whether the vessel 1 has been loaded is provided in the lid27.

An introduction port 29 for introducing outside air is provided in awall of the housing 21, and a check valve 30 is installed at theintroduction port 29. Moreover, the mouthpiece 32 is provided at the tipof the housing 21. The suction port 31 of the mouthpiece 32 is coveredby a cap 32 a when the dry powder inhaler is not being used.

A flange-shaped partition part 33 is formed at the base end of theneedle part 5, and an end of the air introduction flow path 17 passesthrough the partition part 33 and opens out in an outer peripheraldirection of the partition part 33. Moreover, a peripheral wall part 34extends from an outer rim part of the partition part 33 towards thesuction port 31 of the mouth piece 32. The needle part 5 is installedinto the housing 21 by fitting the partition part 33 into the tip partof the housing 21. Through this installation, the axial direction of thehousing 21 and the axial direction of the needle part 5 are aligned withone another.

A remover 35 for lifting the vessel 1 from the base of the holder part22 and removing the vessel 1 is attached to the holder part 22, and alever 36 for lifting the vessel 1 up is formed on the remover 35.

The holder operating part 24 comprises a mechanism part 37 for movingthe holder part 22 back and forth along the axial direction of thehousing 21, and an operating lever for operating the mechanism part 37.The mechanism part 37 comprises a connector 39. One end of the connector39 is connected to the holder part 22 by a hinge 40, and the other endof the connector 39 is connected to the lid 27 by a hinge 41. The lid 27is also used as the above-mentioned operating lever. By opening andclosing the lid 27, the holder part 22 is advanced and retreated alongthe guide part 23.

The point of action of the force for pushing down the lid 27 is shown bythe arrow C in FIG. 7. That is, the distance from the hinge 21A to thepoint of action is made to be longer than the distance from the hinge21A to the hinge 41. As a result, through the lever principle, the lid(operating lever) 27 can be operated by a force smaller than the forcenecessary to pierce the stopper 1 a of the vessel 1 with the needle part5.

Moreover, as shown in FIG. 6, second introduction paths 42 forsupplementary introduction of air are formed in the dry powder inhaler.When sucking the freeze-dried composition that has been made into apowder from the mouthpiece 32, outside air passes through these secondintroduction path 42 and flows to the suction port 31 of the mouthpiece32. As a result, the dry powder inhaler can be used without imposing aburden even by a user (patient) having reduced pulmonary capacity or achild patient. Note that the second introduction paths 42 may beomitted.

Introduction grooves 42 a are provided in the partition part 33 of theneedle part 5 and introduction grooves 42 b are provided in theperipheral wall part 34. By fitting the mouthpiece 32 into theperipheral wall part 34 of the needle part 5, the second introductionpaths 42 are thus formed from the mouthpiece 32 and the introductiongrooves 42 a and 42 b.

A slight gap 43 is formed between the mouthpiece 32 and the housing 21,and one end 44 of the second introduction paths 42 opens out to theoutside via the gap 43, while the other end 45 of the secondintroduction paths 42 opens out into the suction port 31 of themouthpiece 32.

Moreover, as shown in FIG. 6, a wall 47 having vent holes 46 is providedin the suction port 31. Consequently, even in the case that the airimpact applied to the freeze-dried composition 2 is small due to a lackof suction force or the like, and part of the freeze-dried composition 2is not made into a powder, the non-powder part can be made into a powderwhen passing through the vent holes 46 of the wall 47.

Moreover, as shown in FIG. 6(a), a tip opening 17 a of the airintroduction flow path 17 of the needle part 5 is made to be closer tothe freeze-dried composition 2 than a tip opening 16 a of the suctionflow path 16. As a result, dropping of the flow speed of the air thatflows into the vessel 1 from the tip opening 17 a of the airintroduction flow path 17 can be suppressed as much as possible, andhence an effective air impact can be applied to the freeze-driedcomposition 2. Moreover, because the tip opening 16 a of the suctionflow path 16 of the needle part 5 is further from the freeze-driedcomposition 2 than the tip opening 17 a of the air introduction flowpath 17, making of the freeze-dried composition 2 can be made to into afine powder in the vessel 1 as much as possible before being sucked intothe air introduction flow path 16 of the needle part 5.

The dry powder inhaler is used as follows. Firstly, the lid 27 is liftedup to open the removal/insertion port 25 of the housing 21 as in FIG. 7,whereby the holder part 22 is pulled backwards to reach theremoval/insertion port 25 of the housing 21. Next, the vessel 1 isinstalled in the holder part 22 with the stopper 1 a facing forwards.Next, the lid 27 is pushed down to close the removal/insertion port 25of the housing 21 as in FIG. 8, whereby the holder part 22 is pushedtowards the needle part 5 by the connector 39, and the stopper 1 a ofthe vessel 1 is pierced by the tip of the needle part 5, thuscommunicating the suction flow path 16 and the air introduction flowpath 17 of the needle part 5 with the inside of the vessel 1. Next, airin the vessel 1 is sucked from the suction port 31 of the mouthpiece 32through the suction flow path 16 of the needle part 5 by the inhalationpressure of the user (patient). At this time, the inside of the vessel 1becomes a negative pressure and the check valve 30 opens, and outsideair flows into the vessel 1 through the air introduction flow path 17 ofthe needle part 5. As a result, an air impact is generated in the vessel1 and the freeze-dried composition 2 is broken down into fine particles,and the fine particles prepared are delivered into the user's(patient's) lungs from the suction port 31 via the suction flow path 16.After use, the lid 27 is lifted up to pull the holder part 22 back up tothe removal/insertion port 25 of the housing 21, and then the remover 35is lifted up by the lever 36 and the vessel 1 is removed from the holderpart 22.

Even if air is conversely blown into the vessel 1 from the suction port31 of the mouthpiece 32, discharge to the outside of the freeze-driedcomposition 2 made into fine particles is prevented by the check valve30.

As mentioned before, the air flow rate of one inhalation of the user(patient) is generally in a range of 5 to 300 L/min, but with the drypowder inhaler shown in FIGS. 4 to 10, in accordance with therespiratory ability of the user (patient), the volume of the vessel 1has been set to about 5 ml, the bore (diameter) of the air introductionflow path 17 to about 2.5 mm, and the bore (diameter) of the suctionflow path 16 to about 2.5 mm. As a result, the settings are such thatmost of the freeze-dried composition 2 is made into fine particles anddischarged from the suction port 31 through one inhalation of the user(patient).

Other embodiments of the dry powder inhaler (self-inhaling type) areshown in FIGS. 11 to 13.

With the dry powder inhaler (self-inhaling type 4) shown in FIG. 11, anoperating member 48 is provided so as to be freely rotatable in thecircumferential direction of the housing 21 as shown by the arrow. Themechanism part of the holder operating part, which is not shown in thedrawing, comprises a spiral groove and a follower that engages into thesame; when the operating member 48 is rotated, this rotation isconverted to linear movement of the holder part 22 in the axialdirection of the needle part 5. Note that the angle of rotation of theoperator 48 is about 180°.

With the dry powder inhaler (self-inhaling type 5) shown in FIG. 12 andFIG. 13, an annular operating member 49 is installed so as to be freelyrotatable in the housing 21. The mechanism part of the holder operatingpart, which is not shown in the drawing, comprises a feed screw; whenthe operating member 49 is rotated, this rotation is converted to linearmovement of the holder part 22 in the axial direction of the needle part5. The holder part 22 can be withdrawn from the back of the housing 21.

Example 1

72 μg of ‘LipofectAMINE 2000’ which is a cationic gene transfer liposome(manufactured by Invitrogen Corporation) and 24 μl of pEGFP-C2, which isa plasmid DNA (manufactured by Clontech), were blended into 1,200 μl ofOPTI-MEM I Reduced Serum Medium (manufactured by Invitrogen Corporation,modified Eagle's minimum essential medium), and the resultant was mixedand suspended to form a complex in the Medium. The geometric meanparticle diameter of the complex formed was measured with a DynamicLight Scattering Particle Size Analyzer (Electrophoretic LightScattering Spectrophotometer, ELS-8000, manufactured by OtsukaElectronics Co., Ltd.) Subsequently, 100 μl of suspension containing thecomplex formed was added and mixed to 400 μl of aqueous L-leucinesolution (5 mg/ml) in which the L-leucine was dissolved in water inadvance, which aqueous solution was contained in a vessel (trunkdiameter of 18 mm), and 10 samples were prepared in this manner.Thereafter, freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form (cake-like) freeze-dried composition(freeze-dried cake) obtained was calculated. Next, a vessel containingthe non-powder-form freeze-dried composition (freeze-dried cake)obtained was installed in a jet type dry powder inhaler (having abellows body 10 capable of supplying an amount of air of about 20 ml;Embodiment 1, FIG. 1) designed such that the bore of the air jet flowpath 3 was 1.2 mm and the bore of the discharge flow path 4 was 1.8 mm.

It was verified that, by introducing an amount of air of about 20 mlfrom the dry powder inhaler into the vessel (giving an air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec), the non-powder-form freeze-dried cake in the vesselwas made into fine particles, and the fine particles were jetted outfrom the vessel via the discharge flow path 4 in an instant. The fineparticles were collected using a particle size distribution meter(Aerosizer: manufactured by Amherst Process Instrument, Inc., USA; R. W.Niven: Pharmaceutical Technology, 72-78 (1993)) fitted with anAerobreather (manufactured by Amherst Process Instrument, Inc., USA, R.W. Niven: Pharmaceutical Technology, 72-78 (1993)), which is anartificial lung model capable of directly measuring the particle sizedistribution of the particles jetted out from the vessel (measurementconditions: breath rate: 60 L/min, breath volume: 1 L, acceleration:19); the particle size distribution of the fine particles that had beenmade was thus measured, and the mass median aerodynamic diameter (μm±SD)was calculated from the particle size distribution. The geometric meanparticle diameter of particles contained in the suspension in thesuspended-form, the disintegration index, and the mass medianaerodynamic diameter (μm+SD) of the fine particles jetted out from theinhaler are shown in Table 1 for each of the freeze-dried compositions.TABLE 1 Geometric mean Mass median particle aerodynamic Freeze-drieddiameter Disintegration diameter composition (μm) index (μm ± SD, MMAD)LipofectAmine 0.827 0.186 1.762 ± 1.491 2000 + pEGFP-C2 + Leucine

As shown in Table 1, the non-powder-form freeze-dried cake having adisintegration index of 0.186 was disintegrated by the air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec, becoming a fine-particle-form powdered preparation ofmass median aerodynamic diameter of 5 μm or less suitable fortranspulmonary administration. Consequently, it was verified that asample before freeze-drying, even in a non-dissolved form (here, in thesuspension form), can be provided as a freeze-dried composition whichcan be made into fine-particle-form dried powder suitable fortranspulmonary administration by the specific air impact defined in thepresent invention. More specifically, the sample before freeze-drying,even in a non-dissolved form, can be used for the dry powder inhaler fortranspulmonary administration of the present invention, and thustranspulmonary administration can be efficiently carried out. Note thatgenes or antisense molecules capable of offering therapeutic effects bytranspulmonary administration can be introduced into a body by employinga cancer suppression gene p53 or a cystic fibrosis transmembraneconductance regulator (CFTR) instead of the plasmid DNA (pEGFP-C2)employed in the present Example. Thus, it should be considered that thedry powder inhalation system of the present invention can be efficientlyutilized for gene therapy.

Example 2, Comparative Example 1

72 μg of ‘LipofectAMINE 2000’, which is a cationic gene transferliposome (manufactured by Invitrogen corporation) and 10 μg of Oligo-RNA(manufactured by Otsuka Pharmaceutical Co., Ltd.) were mixed andsuspended in the presence of OPTI-MEM I Reduced Serum Medium(manufactured by Invitrogen corporation, modified Eagle's minimumessential medium), to form a complex. The geometric mean particlediameter of the complex formed was measured with a Dynamic LightScattering Particle Size Analyzer (Electrophoretic Light ScatteringSpectrophotometer, ELS-8000, manufactured by Otsuka Electronics Co.,Ltd.).

Subsequently, 100 μl of suspension containing the complex formed wasadded to 400 μl of aqueous L-leucine solution (5 mg/ml) prepared bydissolving L-leucine into water in advance, which aqueous solution wascontained in a vessel (trunk diameter of 18 mm), and 10 samples wereprepared in the same manner, to prepare samples for freeze-drying(Example 2). As a Comparative Example, 400 μl of aqueous solution (5mg/ml) of dextran 40 instead of L-leucine aqueous solution employed inthe above was used for preparing samples for freeze-drying (10 samples)in the same manner as in the above (Comparative Example 1).

Thereafter, freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form (cake-like) freeze-dried composition(freeze-dried cake) obtained was calculated. Next, a vessel containingthe non-powder-form freeze-dried composition (freeze-dried cake)obtained was installed in a jet type dry powder inhaler (having abellows body 10 capable of supplying an amount of air of about 20 ml;Embodiment 1, FIG. 1) designed such that the bore of the air jet flowpath 3 was 1.2 mm and the bore of the discharge flow path 4 was 1.8 mm.

It was verified that, by introducing an amount of air of about 20 mlfrom the dry powder inhaler into the vessel (giving an air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec), the non-powder-form freeze-dried cake in the vesselwas made into fine particles, and the fine particles were jetted outfrom the vessel via the discharge flow path 4 in an instant. The fineparticles were collected using a particle size distribution meter(Aerosizer: manufactured by Amherst Process Instrument, Inc., USA)fitted with an Aerobreather (manufactured by Amherst Process Instrument,Inc., USA) (measurement conditions: breath rate: 60L/min, breath volume:1 L, acceleration: 19), and the particle size distribution of the fineparticles that had been made was thus measured, and the mass medianaerodynamic diameter (μm±SD) was calculated from the particle sizedistribution.

The freeze-dried composition of Comparative Example 1 was not dispersedby the air impact arising through an air speed of about 35 m/sec and anair flow rate of about 40 ml/sec, and hence a mass median aerodynamicdiameter could not be calculated.

The geometric mean particle diameter of particles contained in thesuspension in the suspended-form, the disintegration index, and the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the inhaler are shown in Table 2 for each of the freeze-driedcompositions (Example 2, Comparative Example 1). TABLE 2 Geometric meanMass median particle aerodynamic Freeze-dried diameter Disintegrationdiameter composition (μm) index (μm ± SD, MMAD) Example 2) LipofectAMINE1.19 0.165 1.633 ± 1.496 2000 + Oligo-RNA + Leucine ComparativeExample 1) LipofectAMINE 1.19 0.002 not dispersed 2000 + Oligo-RNA + andthus Dextran 40 unmeasureable

As shown in Table 2, the non-powder-form freeze-dried cake having adisintegration index of 0.165 was disintegrated by the air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec, becoming a fine-particle-form powdered preparation ofmass median aerodynamic diameter of 5 m or less suitable fortranspulmonary administration even if the sample before freeze-dryingwas in the non-dissolved form (here, in the suspension form) as inExample 1.

In contrast thereto, the non-powder-form freeze-dried cake having adisintegration index of 0.002 was neither dispersed nor made into fineparticles by the air impact, and hence was not suitable for providing adry powder preparation for transpulmonary administration.

Examples 3 to 5, Comparative Example 2

360 μl of ‘Superfect’ which is an activate dendrimer molecule (cationicpolymer) for gene transfer (manufactured by Qiagen) and 5 μl ofOligo-RNA (manufactured by Otsuka Pharmaceutical Co., Ltd.) (Example 3,Comparative Example 2) or 24 μg of pEGFP-C2 (manufactured by Clontech)which is a plasmid DNA (Examples 4 and 5) were mixed and suspended inthe presence of 1,200 μg of OPTI-MEM I Reduced Serum Medium(manufactured by Invitrogen corporation, modified Eagle's minimumessential medium), to form a complex. The geometric mean particlediameter of the complex formed was measured with a Dynamic LightScattering Particle Size Analyzer (Electrophoretic Light ScatteringSpectrophotometer, ELS-8000, Otsuka Electronics Co., Ltd.) or a LaserDiffraction/Scattering Particle Size Distribution Analyzer (LaserDiffraction Particle Size Analyzer, SALD-3000J, Shimadzu Corporation).Subsequently, 100 μl of suspension containing the complex formed wasadded to 400 μl of aqueous L-leucine-dissolved solution (5 mg/ml)prepared in advance, which aqueous solution was contained in a vessel(trunk diameter of 18 mm) (Examples 3 and 4), or added to 400 μl ofaqueous lactose-dissolved solution (5 mg/ml) prepared in advance, whichthe aqueous solution was contained in a vessel (trunk diameter of 18 mm)(Example 5) and 10 samples were thus prepared for each Example in thesame manner, to prepare samples for freeze-drying. As a ComparativeExample, 400 μl of aqueous dextran 40-dissolved solution (5 mg/ml)instead of the aqueous L-leucine-dissolved solution employed in Example3 was used to prepare samples for freeze-drying (10 samples) in the samemanner (Comparative Example 2).

Thereafter, freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form (cake-like) freeze-dried composition(freeze-dried cake) obtained was calculated. Next, a vessel containingthe non-powder-form freeze-dried composition (freeze-dried cake)obtained was installed in a jet type dry powder inhaler (having abellows body 10 capable of supplying an amount of air of about 20 ml;Embodiment 1, FIG. 1) designed such that the bore of the air jet flowpath 3 was 1.2 mm and the bore of the discharge flow path 4 was 1.8 mm.

As for the freeze-dried composition obtained according to Examples 3, 4,and 5, it was verified that, by introducing an amount of air of about 20ml from the dry powder inhaler into the vessel (giving an air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec), the non-powder-form freeze-dried cake in the vesselwas made into fine particles, and the fine particles were jetted outfrom the vessel via the discharge flow path 4 in an instant. The fineparticles were collected using a particle size distribution meter(Aerosizer: manufactured by Amherst Process Instrument, Inc., USA)fitted with an Aerobreather (manufactured by Amherst Process Instrument,Inc., USA) (measurement conditions: breath rate: 60 L/min, breathvolume: 1 L, acceleration: 19); the particle size distribution of thefine particles that had been made was thus measured, and the mass medianaerodynamic diameter (μm+SD) was calculated from the particle sizedistribution in the same manner as in Example 1.

In contrast thereto, the non-powder form freeze-dried cake ofComparative Example 2 was not dispersed by the air impact arisingthrough an air speed of about 35 m/sec and an air flow rate of about 40ml/sec, and hence the mass median aerodynamic diameter was not obtained.

The geometric mean particle diameter of particles contained in thesuspension in the suspended-form, the disintegration index, and the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the inhaler are shown in Table 3 for each of the freeze-driedcompositions (Examples 3 to 5, Comparative Example 2). TABLE 3 Geometricmean Mass median particle aerodynamic Freeze-dried diameterDisintegration diameter composition (μm) index (μm ± SD, MMAD) Example3) Superfect + 11.12 0.225 1.578 ± 1.403 Oligo-RNA + Leucine 4)Superfect + 3.74 0.189 1.646 ± 1.420 pEGFP-C2 + Leucine 5) Superfect +3.74 0.080 2.848 ± 1.873 pEGFP-C2 + Lactose Comparative Example 2)Superfect + 11.12 0.003 not dispersed Oligo- RNA + and thus Dextran 40unmeasureable

As shown in Table 3, the non-powder-form freeze-dried cakes having adisintegration index of 0.080 to 0.225, that is, 0.05 or more, weredisintegrated by the air impact arising through an air speed of about 35m/sec and an air flow rate of about 40 ml/sec, becoming afine-particle-form powdered preparations of mass median aerodynamicdiameter of 5 μm or less suitable for transpulmonary administration evenif the sample before freeze-dried was in the non-dissolved form (here,in the suspension form) as in Example 1 and particles contained thereinhad the geometric mean particle diameter of 11 μm and thus were prone toaggregate.

In contrast thereto, the non-powder-form freeze-dried cake having thedisintegration index of 0.003 was neither dispersed nor made into fineparticles by the air impact, hence was not suitable for preparing a drypowder preparation for transpulmonary administration.

Consequently, it was verified that the samples before freeze-drying,even in the non-dissolved form (here, in the suspension form), can beprovided as a freeze-dried compositions which can be made intofine-particle-form dried powders suitable for transpulmonaryadministration by the specific air impact defined in the presentinvention. More specifically, the samples before freeze-drying, even inthe non-dissolved form, can be used for the dry powder inhaler fortranspulmonary administration of the present invention, and thustranspulmonary administration can be efficiently carried out. Note thatgenes or antisense molecules capable of offering curative effects bytranspulmonary administration can be introduced into a body by employinga cancer suppression gene p53 or a cystic fibrosis transmembraneconductance regulator (CFTR) instead of the plasmid DNA (pEGFP-C2)employed in the present Example. Moreover, as Oligo-RNA is a kind ofRNAi (RNA interference) and is a RNA duplex applicable to RNAitechnology, a short duplex RNA may thus be introduced corresponding to atarget gene, whereby a function of a messenger RNA of the target genecan be specifically controlled (suppressed), and hence is applicable toa therapy for lung cancer.

Thus, it should be considered that the dry powder inhalation system ofthe present invention can be efficiently utilized for gene therapy.

Example 6

360 μl of ‘Superfect’, which is an activate dendrimer molecule for genetransfer (manufactured by Qiagen), and 5 μg of Oligo-RNA (manufacturedby Otsuka Pharmaceutical Co., Ltd.) were mixed and suspended in thepresence of 1,200 μg of OPTI-MEM I Reduced Serum Medium (manufactured byInvitrogen corporation, modified Eagle's minimum essential medium), toform a complex. The geometric mean particle diameter of the complexformed was measured with a Laser Diffraction/Scattering Particle SizeDistribution Analyzer (Laser Diffraction Particle Size Analyzer,SALD-3000J, Shimadzu Corporation).

Subsequently, 100 μl of suspension containing the complex formed wasadded to 400 μl of aqueous L-Valine-dissolved solution (2.5 mg/ml)prepared in advance, which aqueous solution was contained in a vessel(trunk diameter of 18 mm), and 10 samples were prepared in the samemanner for each Example, to prepare samples for freeze-drying.Thereafter, freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form (cake-like) freeze-dried composition(freeze-dried cake) obtained was calculated.

Next, a vessel containing the non-powder-form freeze-dried composition(freeze-dried cake) obtained was installed in a jet type dry powderinhaler (having a bellows body 10 capable of supplying an amount of airof about 20 ml; Embodiment 1, FIG. 1) designed such that the bore of theair jet flow path 3 was 1.2 mm and the bore of the discharge flow path 4was 1.8 mm.

It was verified that, by introducing an amount of air of about 20 mlfrom the dry powder inhaler into the vessel (giving an air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec), the freeze-dried composition of Example 6 was madeinto fine particles, and the fine particles were jetted out from thevessel via the discharge flow path 4 in an instant. The fine particleswere collected using a particle size distribution meter (Aerosizer:manufactured by Amherst Process Instrument, Inc., USA) fitted with anAerobreather (manufactured by Amherst Process Instrument, Inc., USA(measurement conditions: breath rate: 60 L/min, breath volume: 1 L,acceleration: 19); the particle size distribution of the fine particlesthat had been made was thus measured, and the mass median aerodynamicdiameter (μm±SD) was calculated from the particle size distribution inthe same manner as in Example 1.

The geometric mean particle diameter of particles contained in thesuspension in the suspended-form, the disintegration index, and the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the inhaler are shown in Table 4 for each of the freeze-driedcompositions. TABLE 4 Geometric mean Mass median particle aerodynamicFreeze-dried diameter Disintegration diameter composition (μm) index (μm± SD, MMAD) 6) Superfect + 13.9 0.275 1.589 ± 1.553 Oligo-RNA + Valine

As shown in Table 4, the non-powder-form freeze-dried cake having adisintegration index of 0.275 was disintegrated by the air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec, becoming a fine-particle-form powdered preparation ofmass median aerodynamic diameter of 5 μm or less suitable fortranspulmonary administration even if the sample before freeze-dried wasin the non-dissolved form (here, in the suspension form) as in Example 1and particles contained therein had the geometric mean particle diameterof about 14 μm and thus were prone to aggregate.

As shown by the results obtained in Examples 2 to 6, it was verifiedthat the samples before freeze-drying, even in the non-dissolved form(here, in the suspension form), can be provided as a freeze-driedcomposition which can be made into fine-particle-form dried powdersuitable for transpulmonary administration by the specific air impactdefined in the present invention. More specifically, the freeze-driedcomposition containing ingredients can be used for the dry powderinhaler for transpulmonary administration of the present invention evenwhen the ingredients are not dissolved or are difficult to dissolve intothe solvent, and thus transpulmonary administration can be efficientlycarried out.

Examples 7 and 8

A solution obtained by dissolving insulin (0.2 mg in Example 7 and 1 mgin Example 8) (Recombinant Human Insulin Crystal, manufactured byBiobras, Brazil; relative activity: 26.4 U/mg) into hydrochloric acidsolution, and a solution obtained by dissolving various carriers asshown in Table 5 into purified water were separately prepared, and thesesolutions were mixed at the proportion shown in Table 5, to form varioussuspensions in the suspended form. The geometric mean particle diameterof particles contained in the suspensions was measured with a LaserDiffraction/Scattering Particle Size Distribution Analyzer (LaserDiffraction Particle Size Analyzer, SALD-3000J, Shimadzu Corporation).

Subsequently, the various suspensions were filled into vessels (trunkdiameter 18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form freeze-dried compositions (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with each non-powder-form freeze-dried composition obtained wasinstalled in a self-inhaling type dry powder inhaler configured suchthat the bore of the air introduction flow path 17 was 1.99 mm and thebore of the suction flow path 16 was 1.99 mm (Embodiment 3, FIG. 3).Using this, the fine particle fraction (%) was calculated with a twinimpinger (manufactured by Copley, UK) (applying an air impact arisingthrough an air speed of about 95 m/sec and an air flow rate of about 295ml/sec to the freeze-dried cake). The geometric mean particle diameterof particles contained in the suspension in the suspended-form, thedisintegration index and the fine particle fraction (%) are shown foreach of the freeze-dried compositions in Table 5. TABLE 5 Geometric meanparticle Freeze-dried diameter Disintegration Fine particle composition(μm) index fraction (%) Example 7) 0.2 mg insulin + 0.52 0.292 95.3% 0.1mg leucine + 0.042 mg arginine (pH 6.5) 8) 1 mg insulin + 0.63 0.23857.9% 0.6 mg phenylalanine + 0.11 mg arginine (pH 6.4)

As can be seen from Table 5, the non-powder-form freeze-driedcompositions (freeze-dried cakes), which showed a disintegration indexof at least 0.238, were easily made into fine particles in the vessel bythe above-mentioned air impact, even though the sample beforefreeze-drying was in the form of containing an active ingredient(insulin) in the non-dissolved form, and it was possible to produce apowdered preparation suitable for transpulmonary administration.

Examples 9 to 11

A solution obtained by dissolving 1 mg of insulin (Recombinant HumanInsulin Crystal, manufactured by Biobras, Brazil; relative activity:26.4 U/mg) into hydrochloric acid solution, and a solution obtained bydissolving 0.5 mg of phenylalanine into purified water were separatelyprepared. These solutions were mixed, and then the pH was adjusted withsodium hydroxide, to form various suspensions in the suspended form. Thegeometric mean particle diameter of particles contained in thesuspensions was measured with a Laser Diffraction/Scattering ParticleSize Distribution Analyzer (Laser Diffraction Particle Size Analyzer,SALD-3000J, manufactured by Shimadzu Corporation).

Subsequently, the various suspensions were filled into vessels (trunkdiameter 18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form freeze-dried compositions (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with each non-powder-form freeze-dried composition obtained wasinstalled in a jet-type dry powder inhaler (having a bellows bodycapable of supplying an amount of air of about 20 ml) configured suchthat the bore of the air introduction flow path was 1.2 mm and the boreof the suction flow path was 1.8 mm. Using this, the fine particlefraction (%) was calculated with a twin impinger (manufactured byCopley, UK) (applying an air impact arising through an air speed ofabout 35 m/sec and an air flow rate of about 40 ml/sec to thefreeze-dried cake). The geometric mean particle diameter of particlescontained in the suspension in the suspended-form, the disintegrationindex and the fine particle fraction (%) are shown for each of thefreeze-dried compositions in Table 6. TABLE 6 Geometric mean particleFreeze-dried diameter Disintegration Fine particle composition (μm)index fraction (%) Example  9) 1 mg insulin + 0.5 mg 3.10 0.39 69.3%phenylalanine (pH 6.0) 10) 1 mg insulin + 0.5 mg 0.55 0.39 75.1%phenylalanine (pH 6.4) 11) 1 mg insulin + 0.5 mg 0.61 0.36 72.0%phenylalanine (pH 6.6)

As can be seen from Table 6, the non-powder-form freeze-driedcompositions (freeze-dried cakes), which showed a disintegration indexof at least 0.36, were easily made into fine particles in the vessel bythe above-mentioned air impact, even though the sample beforefreeze-drying was in the form of containing an active ingredient(insulin) in the non-dissolved form, and it was possible to produce apowdered preparation suitable for transpulmonary administration.

Examples 12 and 13

A solution obtained by dissolving 0.1 mg of insulin (Recombinant HumanInsulin Crystal, manufactured by Biobras, Brazil; relative activity:26.4 U/mg) into hydrochloric acid solution, and a solution obtained bydissolving various carriers as shown in Table 7 into purified water wereseparately prepared. These solutions were mixed, and then the pH wasadjusted with sodium hydroxide, to form various suspensions in thesuspended form. The geometric mean particle diameter of particlescontained in the suspensions was measured with a LaserDiffraction/Scattering Particle Size Distribution Analyzer (LaserDiffraction Particle Size Analyzer, SALD-3000J, Shimadzu Corporation).

Subsequently, the various suspensions were filled into vessels (trunkdiameter 18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form freeze-dried compositions (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with each non-powder-form freeze-dried composition obtained wasinstalled in a self-inhaling type dry powder inhaler configured suchthat the bore of the air introduction flow path 17 was 1.99 mm and thebore of the suction flow path 16 was 1.99 mm (Embodiment 3, FIG. 3).Using this, the fine particle fraction (%) was calculated with a twinimpinger (manufactured by Copley, UK) (applying an air impact arisingthrough an air speed of about 95 m/sec and an air flow rate of about 295ml/sec to the freeze-dried cake). The geometric mean particle diameterof particles contained in the suspension in the suspended-form, thedisintegration index and the fine particle fraction (%) are shown foreach of the freeze-dried compositions in Table 7. TABLE 7 Geometric meanparticle Freeze-dried diameter Disintegration Fine particle composition(μm) index fraction (%) Example 12) 0.1 mg insulin + 0.54 0.115 68.7%0.5 mg Leucyl-valine (pH 6.4) 13) 0.1 mg insulin + 0.67 0.051 58.9% 1.5mg Leucyl-valine (pH 6.5)

As can be seen from Table 7, the non-powder-form freeze-driedcompositions (freeze-dried cakes), which showed a disintegration indexof at least 0.051, were easily made into fine particles in the vessel bythe above-mentioned air impact, even though the sample beforefreeze-drying was in the form of containing an active ingredient(insulin) in the non-dissolved form, and it was possible to produce apowdered preparation suitable for transpulmonary administration.

Example 14

A solution obtained by dissolving 0.1 mg of insulin (Recombinant HumanInsulin Crystal, manufactured by Biobras, Brazil; relative activity:26.4 U/mg) into hydrochloric acid solution, and a solution obtained bydissolving valine into purified water were separately prepared. Thesesolutions were mixed, and then the pH was adjusted to pH 6.5 with sodiumhydroxide, to form various suspensions in the suspended form. Thegeometric mean particle diameter of particles contained in thesuspensions was measured with a Laser Diffraction/Scattering ParticleSize Distribution Analyzer (Laser Diffraction Particle Size Analyzer,SALD-3000J, Shimadzu Corporation).

Subsequently, the various suspensions were filled into vessels (trunkdiameter 18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, manufactured by Leybold). The disintegrationindex of the non-powder-form freeze-dried compositions (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with each non-powder-form freeze-dried composition obtained wasinstalled in a self-inhaling type dry powder inhaler configured suchthat the bore of the air introduction flow path 17 was 1.99 mm and thebore of the suction flow path 16 was 1.99 mm (Embodiment 3, FIG. 3).

Using this, an air impact arising through an air speed of about 1 m/secand an air flow rate of about 17 ml/sec is applied to the non-powderform freeze-dried composition (freeze-dried cake) contained in thevessel, and fine particles generated were directly jetted from theinhaler to an Aerosizer (manufactured by Amherst Process Instrument,Inc., USA) fitted with an Aerobreather (manufactured by Amherst ProcessInstrument, Inc., USA: measurement conditions: breath rate: 1 L/min,breath volum: 0.1 L), which is an artificial lung model capable ofdirectly measuring the particle size distribution of the jettedparticles; the particle size distribution of the fine particles was thusmeasured. From the results, the mass median aerodynamic diameter (μm±SD)of the jetted fine particles was calculated. The geometric mean particlediameter of particle contained in the suspension in non-suspended form,the disintegration index for each of the freeze-dried compositions andthe mass median aerodynamic diameter of the particles jetted out fromthe inhaler are shown in Table 8. TABLE 8 Geometric mean Mass medianparticle aerodynamic Freeze-dried diameter Disintegration diametercomposition (μm) index (μm ± SD, MMAD) 14) 0.1 mg insulin + 0.57 0.2211.875 ± 1.384 0.5 mg Valine

As can be seen from Table 8, the non-powder-form freeze-driedcompositions (freeze-dried cakes), which showed a disintegration indexof 0.221, were easily made into fine particles in the vessel by theabove-mentioned air impact, even though the sample before freeze-dryingwas in the form of containing an active ingredient (insulin) in thenon-dissolved form, and it was possible to produce a powderedpreparation suitable for transpulmonary administration.

Reference Examples 1 to 5

Insulin (Recombinant Human Insulin Crystal, manufactured by Biobras,Brazil; relative activity: 26.4 U/mg) (1 mg, 2 mg), or insulin and anyof various carriers as shown in Table 6, was/were made up to 0.2 ml bydissolving in injection distilled water containing hydrochlolic acid,this was filled into vessels (trunk diameter 18 mm), and freeze-dryingwas carried out using a shelf-type freeze-dryer (Lyovac GT-4,manufactured by Leybold). The disintegration index of thenon-powder-form freeze-dried composition (freeze-dried cake) obtainedwas calculated. Next, a vessel (trunk diameter 18 mm) filled with thenon-powder-form freeze-dried composition obtained was installed in aself-inhaling type dry powder inhaler (Embodiment 3, FIG. 3) designedsuch that the bore of the air introduction flow path 17 was 1.99 mm andthe bore of the suction flow path 16 was 1.99 mm (Embodiment 3, FIG. 3).Using this, the fine particle fraction (%) was calculated with a twinimpinger (manufactured by Copley, UK) (applying an air impact arisingthrough an air speed of about 95 m/sec and an air flow rate of about 295ml/sec to the freeze-dried cake). The disintegration index and the fineparticle fraction (%) are shown in Table 9 for each of the freeze-driedcompositions. TABLE 9 Disintegration Fine particle Freeze-driedcomposition index fraction (%) Ref. 1) 1 mg insulin 0.159 75.0 Ref. 2) 1mg insulin + 1.4 mg leucine 0.145 80.7 Ref. 3) 1 mg insulin + 1.0 mgvaline 0.110 79.4 Ref. 4) 2 mg insulin 0.177 42.4 Ref. 5) 2 mg insulin +1.4 mg leucine 0.137 65.1As can be seen from Table 9, the non-powder-form freeze-driedcompositions (freeze-dried cakes), which showed a disintegration indexof 0.110 or more, were easily made into fine particles in the vessel bythe above-mentioned air impact, with it being possible to produce apowdered preparation suitable for transpulmonary administration.

Reference Examples 6 to 10

1 mg of insulin (Recombinant Human Insulin Crystal, manufactured byBiobras, Brazil; relative activity: 26.4 U/mg) and any of variouscarriers (1.5 mg) as shown in Table 7 were made up to 0.5 ml bydissolving in injection distilled water containing hydrochlolic acid,this was filled into vessels (trunk diameter 18 mm), and freeze-dryingwas carried out using a shelf-type freeze-dryer (Lyovac GT-4,manufactured by Leybold). The disintegration index of thenon-powder-form freeze-dried composition (freeze-dried cake) obtainedwas calculated. Next, a vessel (trunk diameter 18 mm) filled with thenon-powder-form freeze-dried composition obtained was installed in a jettype dry powder inhaler (having a bellows body capable of supplying anamount of air of about 20 ml, Embodiment 1, FIG. 1) designed such thatthe bore of the air jet flow path was 1.2 mm and the bore of thedischarge flow path was 1.8 mm. Using this, an air impact arisingthrough an air speed of about 35 m/sec and an air flow rate of about 40ml/sec is applied to the non-powder form freeze-dried composition(freeze-dried cake) contained in the vessel, and fine particlesgenerated were directly jetted from the inhaler to an Aerosizer(manufactured by Amherst Process Instrument, Inc., USA) fitted with anAerobreather (manufactured by Amherst Process Instrument, Inc., USA:measurement conditions: breath rate: 60 L/min, breath volume: 1 L),which is an artificial lung model capable of directly measuring theparticle size distribution of the jetted particles; the particle sizedistribution of the fine particles was thus measured. From the results,the mass median aerodynamic diameter (μm±SD) of the jetted fineparticles was calculated.

Furthermore, a vessel (trunk diameter 18 mm) filled with thenon-powder-form freeze-dried composition obtained was installed in aself-inhaling type dry powder inhaler designed such that the bore of theair introduction flow path was 1.99 mm and the bore of the suction flowpath was 1.99 mm (Embodiment 3, FIG. 3). Using this, the fine particlefraction (%) was calculated with a twin impinger (manufactured byCopley, UK) (applying an air impact arising through an air speed ofabout 95 m/sec and an air flow rate of 295 ml/sec to the freeze-driedcake).

The disintegration index, the mass median aerodynamic diameter (μm±SD)of the fine particles jetted out from the jet type dry powder inhaler,and the fine particle fraction (%) of the fine particles obtained by theself-inhaling type dry powder inhaler are shown in Table 10 for each ofthe freeze-dried compositions. TABLE 10 Mass median Freeze-dried Dis-diameter composition integration (μm ± SD, Fine particle fraction(%)index MMAD) aerodynamic Reference Examples  6) Insulin + isoleucine0.124 1.759 ± 1.425 71.1  7) Insulin + leucine 0.250 1.954 ± 1.454 74.1 8) Insulin + valine 0.124 2.007 ± 1.438 72.1  9) Insulin +phenylalanine 0.204 1.872 ± 1.477 62.0 10) Insulin + D-mannitol 0.1602.239 ± 1.435 61.2

As shown in Table 10, the non-powder-form freeze-dried compositions(freeze-dried cakes), which showed a disintegration index of 0.124 ormore, were easily made into fine particles in the vessel by the airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec or the air impact arising through an air speedof about 95 m/sec and an air flow rate of 295 ml/sec. Moreover, the meanparticle diameter of the fine particles manufactured by the air impactarising through an air speed of about 95 m/sec and an air flow rate of295 ml/sec was 5 μm or less, and hence it was possible to produce apowdered preparation suitable for transpulmonary administration.

INDUSTRIAL APPLICABILITY

According to the dry powder inhalation system for transpulmonaryadministration of the present invention, a freeze-dried composition canbe made into fine particles down to a size necessary for delivery intothe lungs, and moreover administration of the fine particles into thelungs through inhalation is possible. That is, according to the drypowder inhalation system for transpulmonary administration of thepresent invention, a freeze-dried composition that has been prepared ina non-powder form can be made into fine particles at the time of use(the time of administration), and administered through inhalation at thesame time, and hence a special operation for making the preparation intofine particles becomes unnecessary. Consequently, according to the drypowder inhalation system for transpulmonary administration (preparationsystem) of the present invention, there is no risk of loss during themanufacturing process (deactivation of the drug or collection lossthrough a filling operation) or loss during storage (for exampledeactivation of the drug due to being stored in a fine particle form),or contamination with impurities during the manufacturing process; adesired fixed amount can thus be administered stably. This is useful inparticular with preparations having as an active ingredient a generallyexpensive pharmacologically active substance such as a protein or apeptide.

The proportion of effective particles (fine particle fraction) attainedby the dry powder inhalation system for transpulmonary administration ofthe invention is at least 10%, and can be increased to at least 20%, atleast 25%, at least 30% or at least 35%. U.S. Pat. No. 6,153,224indicates that, with many of prior art dry powder inhalers, theproportion of the active ingredient (particles) to adhere to the lowerportions of the lungs is only about 10% of the amount of the activeingredient inhaled. Further, Japanese Unexamined Patent Publication No.2001-151673 states that the amount of an inhalation powder preparationreaching the lungs (lung reaching proportion) is generally about 10% ofthe drug discharged from the preparation. Therefore, the dry powderinhalation system of the invention is valuable in that it is capable ofachieving a higher proportion of effective particles (fine particlefraction) than prior art powder inhalation preparations.

According to the freeze-dried composition and jet type dry powderinhaler of the present invention, the freeze-dried composition can bemade into fine particles merely by jetting air into the vessel from theair jet flow path using the air pressure-feeding means and thus applyinga slight air impact to the freeze-dried composition. The making intofine particles can thus be carried out at the time of use with an drypowder inhaler having a simple structure and moreover with simplehandling. Moreover, because the dry powder inhaler has a simplestructure, it can be produced with a low manufacturing cost, and hencemass distribution is possible.

Moreover, according to the jet type dry powder inhaler, by adjusting thespeed of compression of the air pressure-feeding means such as a bellowsbody, the amount sucked in of the aerosol (powdered preparation) can beadjusted in accordance with the respiratory ability of the user.Moreover, by using a single integrated needle part, the operation ofpiercing the stopper of the vessel with the needle part becomes simple.

Furthermore, according to the self-inhaling type dry powder inhaler, thefreeze-dried composition can be made into an aerosol (made into fineparticles) through an air impact being generated by the inhalationpressure of the user, and hence the making into fine particles andadministration into the lungs of the freeze-dried composition can becarried out at the same time as the user inhaling, and thus it can beexpected that the drug will be administered in a stable amount with noloss. Moreover, a separate special operation for making into an aerosol(making into fine particles) is unnecessary, and hence handling is easy.Moreover, as with the jet type, by using a single integrated needlepart, the operation of piercing the elastic port stopper of the vesselwith the needle part becomes simple.

According to the dry powder inhaler of the present invention, bypiercing the stopper of the vessel with the tip of the needle parthaving the suction flow path and the air introduction flow path, and airin the vessel then being sucked in from the suction port by theinhalation pressure of the user (patient), air can be made to flow intothe vessel from the air introduction flow path of the needle part, thusapplying an air impact to the freeze-dried composition, and thefreeze-dried composition that has been made into a powder can be suckedin from the vessel.

Moreover, in the case of the dry powder inhaler of the present inventiondisclosed as Embodiment 4 in particular, the following effects areexhibited.

When trying to apply an effective air impact to the freeze-driedcomposition and suck the powder-form freeze-dried composition that hasbeen made into fine particles from the vessel, the cross-sectional areasof the suction flow path and the air introduction flow path must be madelarge, and hence the diameter of the needle part must be made large.

However, in the case of piercing a needle part having a large diameterthrough the stopper, it becomes necessary to hold the vessel securely,and in this state move the vessel towards the needle tip withoutdeviating away from the axis of the needle part, and push the stopperagainst the needle tip with a large force.

As described above, the dry powder inhaler of the present invention thushas a holder part that holds the vessel, a guide part of the holderpart, and a holder operating part having a mechanism part and anoperating member that operates the mechanism part. Therefore, by holdingthe vessel with the holder part, moving the vessel along the axis of theneedle part following the guide part towards the needle tip, andoperating the operating member, it is thus possible to pierce the needlepart through the stopper of the vessel using a relatively low force.

In this way, according to the dry powder inhaler of the presentinvention, the stopper of the vessel can be pierced by the needle parteasily and reliably.

Moreover, if a constitution is adopted in which the housing is formed ina tubular shape, the suction port is formed at a tip part of thehousing, a housing chamber for the vessel is formed in the housing, theneedle part is disposed in the housing so that the needle tip pointstowards the housing chamber, an introduction port for introducingoutside air that communicates with the air introduction flow path of theneedle part is provided in a wall of the housing, and the holder part isadvanced and retreated in the axial direction of the housing in thehousing chamber using the holder operating part, then a pencil-shapeddry powder inhaler can be formed, which is easy to use and convenientlyportable.

Moreover, if the constitution is made to be such that the housing isformed from a housing main body having a removal/insertion port for thevessel in a position in which the holder part is retreated, and a lidfor the removal/insertion port that is connected to the housing mainbody by a hinge, the holder operating part has a mechanism part whichmoves the holder part forwards when the lid is pushed down and theremoval/insertion port closed, and moves the holder part backwards whenthe lid is lifted up and the removal/insertion port opened, and the lidis used as the operating member of the mechanism part, then themechanism part of the holder operating part can be simplified and in themanufacturing cost. Moreover, the removal/insertion port of the vesselcan be closed at the same time as piercing the stopper of the vesselwith the needle tip, and hence use becomes easier.

1. A freeze-dried composition for transpulmonary administration preparedby freeze-drying a composition liquid containing ingredients in anon-dissolved form which has the following properties (i) to (iii): (i)a non-powder cake-like form, (ii) a disintegration index of 0.05 ormore, and (iii) becoming fine particles having a mean particle diameter(mass median aerodynamic diameter) of 10 microns or less or a fineparticle fraction of 10% or more upon receipt of an air impact having anair speed of at least 1 m/sec and an air flow rate of at least 17ml/sec.
 2. The freeze-dried composition according to claim 1, wherein ahigh-molecular-weight drug is contained as an active ingredient.
 3. Amethod of manufacturing a dry powdered preparation for transpulmonaryadministration, comprising: introducing air into a vessel to apply to afreeze-dried composition an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec using a device capableof applying said air impact to the freeze-dried composition in thevessel, thereby making said freeze-dried composition into fine particleshaving a mean particle diameter (mass median aerodynamic diameter) of 10microns or less or a fine particle fraction of 10% or more; thefreeze-dried composition prepared by freeze-drying a composition liquidcontaining ingredients in a non-dissolved form and having the followingproperties: (i) a non-powder cake-like form, (ii) a disintegration indexof 0.05 or more, and (iii) becoming fine particles having a meanparticle diameter of 10 microns or less or a fine particle fraction of10% or more upon receipt of the air impact.
 4. The method ofmanufacturing a dry powdered preparation for transpulmonaryadministration according to claim 3, wherein the freeze-driedcomposition contains a high-molecular-weight drug as an activeingredient.
 5. The method of manufacturing a dry powdered preparationfor transpulmonary administration according to claim 3 comprisingpulverizing a freeze-dried composition into fine particles using a drypowder inhaler described under item (A) or (B) as a device: (A) a drypowder inhaler for transpulmonary administration, being a device usedfor making a freeze-dried composition that has been housed in non-powderform in a vessel into fine particles, and administering the resultingfine particles to a user by inhalation, comprising a needle part havingan air jet flow path, a needle part having a discharge flow path, airpressure-feeding member for feeding air into the air jet flow path ofsaid needle part, and an inhalation port that communicates with thedischarge flow path of said needle part, and characterized by beingconstituted such that a stopper that seals up said vessel is pierced bysaid needle parts, thus communicating the air jet flow path and thedischarge flow path with the inside of said vessel, and air is jettedinto said vessel through said air jet flow path using said airpressure-feeding member, thus pulverizing said freeze-dried compositioninto fine particles by the impact of the jetted air, and discharging thefine particles obtained from the inhalation port via said discharge flowpath, or (B) a dry powder inhaler for transpulmonary administration,being a device used for making a freeze-dried composition that has beenhoused in non-powder form in a vessel into fine particles, andadministering the resulting fine particles to a user by inhalation,comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path, and characterized by beingconstituted such that, in a state in which a stopper sealing up saidvessel has been pierced by said needle parts, through the inhalationpressure of the user, air in said vessel is inhaled from said inhalationport, and at the same time outside air flows into said vessel, at anegative pressure, through said air introduction flow path, and as aresult said freeze-dried composition is pulverized into fine particlesby the impact of the air flowing in, and the fine particles obtained aredischarged from the inhalation port through said suction flow path.
 6. Adry powder inhalation system for transpulmonary administration, using acombination of: (1) a vessel housing a freeze-dried composition preparedby freeze-drying a composition liquid containing ingredients in anon-dissolved form, and has: (i) a non-powder cake-like form, (ii) adisintegration index of 0.05 or more, and (iii) a property of becomingfine particles having a mean particle diameter (mass median aerodynamicdiameter) of 10 microns or less or a fine particle fraction of 10% ormore upon receiving an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec; and (2) a devicecomprising a member capable of applying said air impact to thefreeze-dried composition in said vessel, and a member for dischargingthe powder-form freeze-dried composition that has been made into fineparticles.
 7. The dry powder inhalation system for transpulmonaryadministration according to claim 6, wherein the vessel and the deviceare used in combination at the time of inhalation.
 8. The dry powderinhalation system for transpulmonary administration according to claim6, wherein the freeze-dried composition contains a high-molecular-weightdrug as an active ingredient.
 9. The dry powder inhalation system fortranspulmonary administration according to claim 6, wherein the deviceis: A) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation, comprising aneedle part having an air jet flow path, a needle part having adischarge flow path, air pressure-feeding member for feeding air intothe air jet flow path of said needle part, and an inhalation port thatcommunicates with the discharge flow path of said needle part, andcharacterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding member, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path, or B) a dry powder inhaler fortranspulmonary administration, being a device used for making afreeze-dried composition that has been housed in non-powder form in avessel into fine particles, and administering the resulting fineparticles to a user by inhalation, comprising a needle part having asuction flow path, a needle part having an air introduction flow path,and an inhalation port that communicates with said suction flow path,and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.
 10. A transpulmonary administrationmethod comprising: making a freeze-dried composition into fine particleshaving a mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more by applying an air impact having an air speed ofat least 1 m/sec and an air flow rate of at least 17 ml/sec to thefreeze-dried composition at the time of use, and administering theresulting fine particle powder to a user by inhalation; the freeze-driedcomposition being prepared by freeze-drying a composition liquidcontaining ingredients in a non-dissolved form and having the followingproperties: (i) a non-powder cake-like form, (ii) a disintegration indexof 0.05 or more, and (iii) becoming fine particles having a meanparticle diameter of 10 microns or less or a fine particle fraction of10% or more upon receipt of the air impact.
 11. The transpulmonaryadministration method according to claim 10, wherein the freeze-driedcomposition is housed in a vessel, and the fine particle powder areprepared using a device comprising a member capable of applying the airimpact to the freeze-dried composition in the vessel and a member fordischarging the resulting fine particle powder-form freeze-driedcomposition out of the vessel.
 12. The transpulmonary administrationmethod according to claim 10, wherein the freeze-dried compositioncontains a high-molecular-weight drug as an active ingredient.
 13. Thetranspulmonary administration method according to claim 11, using a drypowder inhaler described under item (A) or (B) as the device: (A) a drypowder inhaler for transpulmonary administration, being a device usedfor making a freeze-dried composition that has been housed in non-powderform in a vessel into fine particles, and administering the resultingfine particles to a user by inhalation, comprising a needle part havingan air jet flow path, a needle part having a discharge flow path, airpressure-feeding member for feeding air into the air jet flow path ofsaid needle part, and an inhalation port that communicates with thedischarge flow path of said needle part, and characterized by beingconstituted such that a stopper that seals up said vessel is pierced bysaid needle parts, thus communicating the air jet flow path and thedischarge flow path with the inside of said vessel, and air is jettedinto said vessel through said air jet flow path using said airpressure-feeding member, thus pulverizing said freeze-dried compositioninto fine particles by the impact of the jetted air, and discharging thefine particles obtained from the inhalation port via said discharge flowpath, or (B) a dry powder inhaler for transpulmonary administration,being a device used for making a freeze-dried composition that has beenhoused in non-powder form in a vessel into fine particles, andadministering the resulting fine particles to a user by inhalation,comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path, and characterized by beingconstituted such that, in a state in which a stopper sealing up saidvessel has been pierced by said needle parts, through the inhalationpressure of the user, air in said vessel is inhaled from said inhalationport, and at the same time outside air flows into said vessel, at anegative pressure, through said air introduction flow path, and as aresult said freeze-dried composition is pulverized into fine particlesby the impact of the air flowing in, and the fine particles obtained aredischarged from the inhalation port through said suction flow path. 14.Use of a freeze-dried composition for transpulmonary administration byinhalation, the freeze-dried composition prepared by freeze-drying acomposition liquid containing ingredients in a non-dissolved form andhaving the following properties: (i) a non-powder cake-like form, (ii) adisintegration index of 0.05 or more, and (iii) becoming fine particleshaving a mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate of at least 17 ml/sec,and being used by forming into fine particles having said mean particlediameter or said fine particle fraction.
 15. The use of a freeze-driedcomposition for transpulmonary administration according to claim 14,wherein the freeze-dried composition is housed in a vessel, and the fineparticles are prepared using a device comprising a member capable ofapplying the air impact to the freeze-dried composition in the vesseland a member for discharging the resulting fine particle powder-formfreeze-dried composition out of the vessel.
 16. The use of afreeze-dried composition for transpulmonary administration according toclaim 14, wherein the freeze-dried composition contains ahigh-molecular-weight drug as an active ingredient.
 17. Use of afreeze-dried composition for manufacture of a dry powdered preparationfor transpulmonary administration by inhalation, the freeze-driedcomposition having the following properties: (i) being prepared byfreeze drying a composition liquid containing ingredients in thenon-dissolved form, (ii) a non-powder cake-like form, (iii) adisintegration index of 0.05 or more, and (iv) becoming fine particleshaving a mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate of at least 17 ml/sec,and being used by forming into fine particles having said mean particlediameter or said fine particle fraction at the time of use.
 18. The useof a freeze-dried composition for manufacture of a dry powderedpreparation for transpulmonary administration by inhalation according toclaim 17, wherein the freeze-dried composition contains ahigh-molecular-weight drug as an active ingredient.
 19. The use of afreeze-dried composition for manufacture of a dry powdered preparationfor transpulmonary administration according to claim 17, wherein thefreeze-dried composition is housed in a vessel, and the fine particlesare prepared by using a device comprising a member for applying aprescribed air impact to the freeze-dried composition housed in thevessel and a member for discharging the resulting fine particle powderform freeze-dried composition out of the vessel.
 20. Use of acomposition liquid containing ingredients in the non-dissolved form formanufacture of a freeze-dried composition having the followingproperties, which is used for manufacture of dry powdered preparationfor transpulmonary administration: (i) a non-powder cake-like form, (ii)a disintegration index of 0.05 or more, and (iii) becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receipt of an air impacthaving an air speed of at least 1 m/sec and an air flow rate of at least17 ml/sec, and being used by forming into fine particles having saidmean particle diameter or said fine particle fraction at the time ofuse.
 21. The use of a composition liquid containing ingredients in thenon-dissolved form according to claim 20, wherein the freeze-driedcomposition contains a high-molecular-weight drug as an activeingredient
 22. The use of a composition liquid containing ingredients inthe non-dissolved form according to claim 20, wherein the freeze-driedcomposition is housed in a vessel, and the fine particles are preparedby using a device comprising a member for applying a prescribed airimpact to the freeze-dried composition housed in the vessel and a memberfor discharging the resulting fine particle powder form freeze-driedcomposition out of the vessel.